Yeast Recombinant Hepatitis Research Articles

New Russian Trivalent Hepatitis B Vaccine (Bubo<sup>®</sup>-Unigep): Clinical Study Results

Relevance. Currently, there is no registered vaccine against the hepatitis B virus (HBV) mutant G145R worldwide, which justifies the need to develop a new generation of vaccines due to large-scale immunization against hepatitis B and the accumulation of escape mutants of the virus.The aim of the study was a comparative assessment of the immunogenicity, reactogenicity and safety of Bubo®-Unigep (trivalent hepatitis B recombinant yeast vaccine) and the drug Hepatitis B recombinant yeast vaccine.Materials and methods. To assess the main characteristics of the new trivalent vaccine Bubo®-Unigep (CJSC NPC «COMBIOTECH»), a doubleblind, comparative, randomized, multicenter clinical trial was conducted in two parallel groups in previously unvaccinated individuals in an adult healthy population (n = 166) according to a protocol developed by the contract research organization «R&D Pharma».Results. The assessment of hematological and biochemical parameters during screening and the administration of vaccine preparations showed that in the individuals included in the study, the studied indicators were within the boundaries of the normal range. According to the criteria for assessing safety and efficacy, both drugs had low reactogenicity, no serious adverse events were registered. The results of a comparative analysis of the concentrations of antibodies to HBsAg determined after a full course of immunization with Bubo®-Unigep vaccine or recombinant yeast Hepatitis B vaccine showed that both drugs effectively induced a humoral immune response (anti-HBs) with seroprotection rates of 96.3% and 92.6%.Conclusion. The inclusion of the relevant HBV serotypes (ay and ad) and the mutant antigen G145R in the composition of the new polyvalent vaccine Bubo®-Unigep contributes to the expansion of the spectrum of specificity of the immune response, and, consequently, more effective vaccination of hepatitis B.

Inoculation effects of recombinant yeast hepatitis B vaccine used in neonates

This study aimed to find out the immune response effects and side effects after recombinant yeast hepatitis B vaccine inoculation in neonates. All 203 neonates were divided into three groups: 25 subjects in group A whose mother was HBsAg(+) HBeAg(+), 43 subjects in group B whose mother was HBsAg(+) HBeAg(-) and 135 subjects in group C whose mother was HBsAg(-). The immune response effects at 12th month after first inoculation were compared and side effects were observed. Non-responders received re-immunization at 12th month after first inoculation and immune response effects were compared at 36th month after first inoculation. There was no significant difference of anti-HBsAg(+) neonates proportion between group “A plus B” and group C, neither between group B and C at 12th month after innoculation. But there were significant differences between group A and B or C. There were 3, 1 and 0 HBsAg(+) neonates in 3 groups at 12th month after the first inoculation. There were 5, 2 and 10 infants identified as non-responders and received re-immunization in 3 groups. Among of the “non-responders” significant differences were found in anti-HBsAg(+) proportion between group “A plus B” and group C at 36th month. Only 1 HBsAg(+) was found in group A at 36th month. All subjects of responders remained anti-HBsAg(+) at 36th month. No serious side effects were found. This China-made recombinant yeast hepatitis B vaccination is safe and effective to prevent HBV vertical transmission. HBsAg and HBeAg status of mother perhaps affect the immune response effects on neonates. Key words: Recombinant yeast hepatitis B vaccine, neonates.

Effect of GM-CSF in combination with hepatitis B vaccine on revacination of healthy adult non-responders

To assess the immune effects and safety of using GM-CSF with the yeast-recombinant hepatitis B virus (HBV) vaccine for the re-vaccination of healthy adults who did not respond to a previous vaccination. Study participants included 1784 healthy adults and 100 individuals diagnosed as non-responders. These healthy non-responders were randomly assigned to one of the three treatment groups: Group A (34 individuals) was given 150 microg of granulocyte-macrophage colony stimulating factor (GM-CSF) the first day, then 20 microg of the vaccine; Group B (33 individuals) was given 40 microg of the vaccine only; and, group C (33 individuals) was injected with 20 microg of vaccine each time. All participants were injected three times, at time of study enrollment and one and six months later. Anti-HB surface antigen (HBs) antibody titers were tested before treatment and at one (T1), two (T2) and eight (T8) months post-first injection. At T1, the rate of anti-HBs antibody(+) in groups A, B and C was 26.47%, 48.48% and 18.18%, respectively (p = .027). At T8, the seropositive rate of group A (64.71%) and group B (75.76%) was significantly higher than in group C (39.39%) (p = .011); the geometric mean of the antibody titer for groups A and B was higher than for group C (p = .0173). All three treatments were safe and well-tolerated. Augmentation of the vaccine dose and co-administration of GM-CSF and the standard vaccine dose are effective for HBV vaccine non-responders. In fact, changing the vaccine dose had a better seropositive response than injecting the vaccine in combination with GM-CSF.

Over a decade of experience with a yeast recombinant hepatitis B vaccine

Experience with the yeast recombinant hepatitis B vaccine Engerix™-B now exceeds 10 years. We reviewed published studies on this vaccine. These show the vaccine to be safe, causing mostly only minor local symptoms and to be highly immunogenic both in monitored clinical trials and under field conditions. Engerix™-B consistently elicits high geometric mean antibody titres and a high protective efficacy has been established in three groups at high-risk of hepatitis B infection, homosexual men, institutionalised mentally handicapped subjects and neonates of chronic carrier mothers. The profile of the recombinant hepatitis B vaccine in certain high-risk groups and immuno compromised people is discussed. Finally we present updated post marketing surveillance data based on 496 million distributed doses of vaccine.

Characterization of Recombinant Hepatitis B Surface Antigen Using Surface Plasmon Resonance

□ Two commercial monoclonal antibodies were shown to interact with distinct epitopes within the major antigenic a determinant region of yeast recombinant hepatitis B surface antigen (rHBsAg) particles, contained in the hepatitis B vaccine, by using the surface plasmon resonance phenomenon on a BIAcore system. Apparent avidity for these antibodies were compared among different rHBsAg batches, showing the consistency of these epitopes. Furthermore, the effect of the alteration of these epitopes, achieved by chemical modifications, was readily reflected by changes in the apparent avidity for these antibodies. The procedures used in the present study provide a novel and efficient way to characterize rHBsAg particles present in different hepatitis B vaccine products.

Two hundred years of vaccination

There are real or potential difficulties with all vaccines. There may be problems with attenuation of live vaccines, with possible risks for vaccinees or their contacts. With non-infectious vaccines, there may be problems in identifying and preserving the immunogenic components and of ensuring correct presentation of the antigens so that the appropriate immune response is stimulated. With all vaccines, there are potential problems of delivery and storage, particularly in tropical climates. In this respect, the WHO Programme of Expanded Immunization is building on experience gained during the Smallpox Eradication Campaign to facilitate widespread use of vaccines. There are still problems caused by, for example, influenza virus, human immunodeficiency virus (HIV), and various respiratory and enteric pathogens which have variable and/or multiple serotypes, and also by malaria, but progress is being made. Various vaccines are being tested against typhoid, cholera and rotavirus gastroenteritis [[1]xPlotkin, S and Fantini, B eds. See all References, [8]xThe legacy of Jenner. Levine, MM. Brit Med J. 1996; 312: 1177–1178Crossref | PubMedSee all References], and considerable attention is being paid to a synthetic subunit vaccine for malaria [9xMalaria – advances in vaccines. Targett, GAT. Curr Opin Infect Dis. 1995; 8: 322–327Crossref | Scopus (6)See all References[9]. Various HIV vaccines are being developed, and the recent isolation of apparently naturally attenuated mutants of HIV which lack the nef gene suggests they may be developed into attenuated vaccines [10xReconsidering an attenuated vaccine for AIDS. Beale, AJ. Lancet. 1996; 347: 344–345Abstract | PubMed | Scopus (3)See all References[10].Recombinant DNA technology has already made a considerable impact through the successful yeast recombinant hepatitis B vaccine [[1]xPlotkin, S and Fantini, B eds. See all References, [11]xProgress on the control of hepatitis B infection through immunization. Kane, MA. Gut. 1993; 34 (suppl): 10–12Crossref | Scopus (40)See all References], and it is appropriate that smallpox vaccine still has a role to play. Infectious vaccinia recombinant vaccines which express the immunogenic glycoprotein of rabies virus are proving very successful in Europe for oral immunization of foxes, the principal wildlife reservoir of rabies [12xThe development and use of a vaccinia–rabies recombinant oral vaccine for the control of wildlife rabies. Pastoret, PP and Brochier, B. Epidemiol Infect. 1996; 116: 235–240Crossref | PubMedSee all References[12]. Although there are reservations about the widespread use of recombinant vaccinia vaccines, particularly in humans, the technology is being transferred to other poxviruses. Candidate mammalian vaccines are being developed using recombinant canarypox vectors which induce good immune responses although they do not replicate in mammalian cells [[1]xPlotkin, S and Fantini, B eds. See all References, [13]xNon-replicating expression vectors : applications in vaccine development and gene therapy. Limbach, K and Paoletti, E. Epidemiol Infect. 1996; 116: 241–256Crossref | PubMedSee all References].Considerable interest is also being shown in ‘DNA vaccines’ [14xDNA vaccines. McDonnell, WM and Askari, FK. New Eng J Med. 1996; 334: 42–45Crossref | PubMed | Scopus (155)See all References[14]. These comprise the appropriate gene inserted into a plasmid carrier which, when injected into the body, is taken up by host cells. The viral gene is expressed and the antigen preferentially stimulates cell-mediated immunity. By appropriate use of reverse transcriptase, recombinant DNA vaccines are being developed for RNA virus infections, particularly influenza.Jenner's pioneer work on smallpox vaccine was not immediately extended to the control of other infections. However, vaccines have made a significant impact in developed countries, through the control of, for example, measles, diphtheria, tetanus and polio, and the widespread use of these and other vaccines in developing countries should have similar effects. There are still problems with infectious diseases, however, and current vaccine research may help to solve these. Increasing concern about antibiotic-resistant bacteria and the slow rate of development of antiviral drugs emphasizes the ‘truism’ that prevention is better than cure; the ultimate goal should be eradication. This has been achieved for smallpox [5xFenner, F, Henderson, DA, Arita, I, Jezek, Z, and Ladnyi, ID. See all References[5], and is achievable for polio by the year 2000 by mass vaccination [15xMass polio vaccination; eradication by 2000 is a realistic goal. Chander, J and Subrahmanyan, S. Brit Med J. 1996; 312: 1178–1179Crossref | PubMedSee all References[15].

Molecular epidemiology of hepatitis B virus vaccine variants in Singapore

Perinatal infection with variants of hepatitis B virus occurs despite combined immunoprophylaxis with hepatitis B immunoglobulin and currently licensed plasma-derived and recombinant yeast hepatitis B vaccines. Several variants have been detected during a large study of infants born to carrier mothers in Singapore. The most frequent variant was a virus in which a single amino acid substitution Gly to Arg occurred at amino acid position 145 of the outer protein coat of the virus. Similar mutations have been described in Italy, Japan, the USA and a number of other countries. The emergence of antibody escape mutants is a cause for concern for the detection of virus and possibly for future immunization programmes.

Accelerated schedule of hepatitis B vaccination in patients with hemophilia

Early development of immunity after hepatitis B vaccination is particularly important for patients such as hemophiliacs, at high risk for acquiring hepatitis B from potentially infectious plasma-derived concentrates. The purpose of this study was to evaluate whether or not protective antibody titers could be achieved quickly and maintained in hemophiliacs by an accelerated vaccination schedule. A yeast-recombinant hepatitis B vaccine (Engerix B, SKF Ritt) was given subcutaneously in the deltoid region and repeated 2 and 6 weeks later to 85 hemophiliacs negative for hepatitis B virus (HBV) markers. After the first 22 patients had been enrolled, a modification of the schedule involving a fourth booster dose 24 weeks after the first dose of vaccine was applied to the next 63 consecutive vaccines. Fifty-three percent of vaccinees had antibody titers to hepatitis B surface antigen (anti-HBs > or = 10 mlU/ml) by week 6, even though the mean titers of anti-HBs were somewhat lower than those achieved historically in normal individuals. The protection rate had increased to 87% by week 10, one month after the third dose of vaccine, and to 93% by week 24. One year after starting vaccination, the rate for the vaccinees who did not receive the fourth booster dose was 71%, and 96% for those who did receive the fourth dose, with only 2 patients not responding despite the booster dose. It is concluded that even though the accelerated schedule of immunization produced rapidly high rates of protective antibody titers, a booster dose is required to obtain higher titers and provide more persistent immunity.

Structural relationships between hepatitis B surface antigen in human plasma and dimers from recombinant vaccine: a monoclonal antibody study

Ten monoclonal antibodies were obtained from mice immunized with a yeast recombinant hepatitis B vaccine. They were selected at an early stage for their ability to bind to native surface antigen particles (HBsAg) in human plasma. All antibodies recognized conformational epitopes which were destroyed completely or almost completely by reduction of disulphide bridges. They were divided into five epitope groups by their competition for binding to recombinant S protein, though epitopes within each group are not identical. Recombinant S protein migrated on SDS-PAGE in the absence of reducing agents as a mixture of monomers and dimers/oligomers. Sucrose gradient analysis suggests that all these forms are co-aggregated into HBsAg-like particles. On Western blots, all ten antibodies either bound only to dimers/oligomers or strongly preferred them over monomers. The results suggest that, of the antibodies produced in response to recombinant vaccine in mice, most of those which bind strongly to 'native' HBsAg particles in human plasma recognize surface structures created by interaction between two subunits.

Comparative safety and immunogenicity of yeast recombinant hepatitis B vaccines containing S and pre-S2 + S antigens

One hundred and four healthy, hepatitis B virus (HBV) seronegative males were enrolled in a single blind, randomized pilot study to compare antibody and clinical responses to a yeast recombinant pre-S2+S vaccine and a yeast recombinant S antigen vaccine (Recombivax HB®). Participants received either a 12, 24 or 48 μg dose of pre-S2+S vaccine (with a 1:5 ratio by weight of pre-S2 and S antigens) or a 10 μg dose of Recombivax HB® by intramuscular injection at 0, 1 and 6 months; their serological and biochemical responses were measured at 0, 1, 2, 3, 6 and 7 months, while their clinical responses were monitored for 5 days after each injection. The proportion of vaccinees with minor local or systemic complaints (mainly sore arm, malaise, myalgia, fatigue) and the proportion developing antibody to surface antigen (anti-HBs) were similar for all vaccine groups. Transient elevations in alanine aminotransferase occurred infrequently. By 7 months almost all vaccinees developed anti-HBs, but titres were generally higher among recipients of pre-S2+S vaccine. Antibody to pre-S2 antigen developed in 70–75% by 2 months and in 91–96% by 7 months. These data imply that the recombinant yeast pre-S2+S vaccine is as well tolerated and as immunogenic as Recombivax HB®. Further studies are being conducted to assess antibody responses in larger numbers of healthy adults as well as in special populations with sub-optimal responses to currently licensed hepatitis B vaccines.

Lack of Response to Recombinant Hepatitis B Vaccine in Nonresponders to the Plasma Vaccine

Yeast recombinant hepatitis B vaccine was administered to 25 nonresponders to the plasma-derived hepatitis B vaccine. After three 10-μg doses, nine subjects (36%) produced levels of antibodies to hepatitis B surface antigen (antiHBs) of less than 2.1 sample ratio units (SRU) (nonresponders), and five (20%) developed anti-HBs of 2.1 to 9.9 SRU (hyporesponders); anti-HBs levels of 10 SRU or greater were detected at least once in 11 vaccinees (44%), but by the sixth and 12th months after the last vaccination, only three and one of these responders, respectively, still maintained anti-HBs values of 10 SRU or greater. In these 25 subjects HLA subtyping showed a high prevalence of DR7, B8, and the combinations of DR3 and DR7 and DR4 and DR7. Our findings indicate that the yeast recombinant hepatitis B vaccine was not effective in eliciting a sustained anti-HBs response in nonresponders to the plasma hepatitis B vaccine. ( JAMA 1988;260:1734-1738)

Recombinant‐yeast‐derived hepatitis b vaccine in healthy adults: Safety and two‐year immunogenicity of early investigative lots of vaccine

We tested the safety and long-term immunogenicity of two of the early investigative lots of a recombinant-yeast-derived hepatitis B vaccine in immunocompetent adults. Three 10-micrograms doses of recombinant hepatitis B vaccine (Merck Sharp & Dohme Research Laboratories, West Point, PA) were administered by deltoid intramuscular injection at time 0, 1, and 6 months to 65 seronegative adult health workers. Following a complete three-injection course, 98% of vaccinees acquired anti-HBs, 97% at levels greater than 10 mlU/ml, and 95% maintained such "protective" antibody levels at 1 year. At 2 years, 93% retained antibody, but only 68% had levels greater than 10 mlU/ml. In those who responded to vaccination by achieving any detectable level of antibody, the peak geometric mean titer of anti-HBs, measured at 9 months, was 741 +/- 6 mlU/ml; the geometric mean titer fell to 348 +/- 6 at 1 year and to 66 +/- 7 at 2 years. Side effects were trivial, and levels of yeast antibody, as measured by radioimmunoassay, were not changed from prevaccine levels. No serious adverse effects were encountered, and neither type B nor non-B hepatitis occurred in any vaccine. These findings demonstrate that the recombinant yeast hepatitis B vaccine is safe and immunogenic but that 10 micrograms of the early investigative lots of the recombinant vaccine is less immunogenic than 20 micrograms of the plasma-derived vaccine. Recipients of early investigative vaccine lots should be considered for booster vaccination with currently available, more immunogenic vaccine lots.

Immunogenicity of a yeast‐recombinant hepatitis B vaccine in high‐risk children

Horizontal transmission of hepatitis B virus (HBV) from illicit drug users to their contacts, including young children, can be prevented by active immunization against HBV. Yeast-recombinant hepatitis B vaccines are now available for this purpose, but their potential efficacy in such high-risk contacts has not yet been evaluated. Therefore we gave 20 mcg of a recombinant yeast-derived hepatitis B vaccine to 38 children who were at high risk for HBV infection because they had been institutionalized in a community for drug users in which 8.7% of the occupants are carriers. After third dose of vaccine (at 0, 1, and 6 months), all children had anti-HBs responses with titers of 10 mIU/ml or more, with 81% showing responses greater than 1,000 mIU/ml. At 12 months, the percentage of anti-HBs-positive children was 100%, and the percentage of children with anti-HBs higher than 1,000 mIU/ml was 56%. None of the children developed HBV infection during follow-up. Hence the recombinant vaccine was immunogenic, with percentages of seroconversion and anti-HBs titers comparable with those attained in other categories of high-risk children with plasma-derived vaccines.

Lack of Response to Recombinant Hepatitis B Vaccine in Nonresponders to the Plasma Vaccine

Yeast recombinant hepatitis B vaccine was administered to 25 nonresponders to the plasma-derived hepatitis B vaccine. After three 10-micrograms doses, nine subjects (36%) produced levels of antibodies to hepatitis B surface antigen (anti-HBs) of less than 2.1 sample ratio units (SRU) (nonresponders), and five (20%) developed anti-HBs of 2.1 to 9.9 SRU (hyporesponders); anti-HBs levels of 10 SRU or greater were detected at least once in 11 vaccinees (44%), but by the sixth and 12th months after the last vaccination, only three and one of these "responders," respectively, still maintained anti-HBs values of 10 SRU or greater. In these 25 subjects HLA subtyping showed a high prevalence of DR7, B8, and the combinations of DR3 and DR7 and DR4 and DR7. Our findings indicate that the yeast recombinant hepatitis B vaccine was not effective in eliciting a sustained anti-HBs response in nonresponders to the plasma hepatitis B vaccine.

Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission

Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission

Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission.

A yeast-recombinant hepatitis B vaccine was licensed recently by the Food and Drug Administration and is now available. To assess the efficacy of the yeast-recombinant vaccine, we administered the vaccine in combination with hepatitis B immune globulin to high-risk newborns. If infants whose mothers were positive for both hepatitis B surface antigen and the e antigen receive no immunoprophylaxis, 70% to 90% become infected with the virus, and almost all become chronic carriers. Among infants in this study who received hepatitis B immune globulin at birth and three 5-micrograms doses of yeast-recombinant hepatitis B vaccine, only 4.8% became chronic carriers, a better than 90% level of protection and a rate that is comparable with that seen with immune globulin and plasma-derived hepatitis B vaccine. These data suggest that, in this high-risk setting, the yeast-recombinant vaccine is as effective as the plasma-derived vaccine in preventing hepatitis B virus infection and the chronic carrier state.

Yeast recombinant hepatitis B vaccine in perinatal hepatitis B virus transmission: A preliminary report

Yeast recombinant hepatitis B vaccine in perinatal hepatitis B virus transmission: A preliminary report

Recombinant yeast hepatitis B vaccine compared with plasma-derived vaccine: Immunogenicity and effect of a booster dose

The immunogenic effect of recombinant yeast and plasma-derived hepatitis B vaccines administered at 0, 1 and 6 months was evaluated in 334 seronegative health professionals. The seroconversion rates following 10 micrograms, 5 micrograms and 2.5 micrograms doses of recombinant vaccine were similar to those observed after 20 micrograms doses of plasma-derived vaccine. The geometric mean antibody titres (G.M.T.) induced by 10 micrograms and 5 micrograms doses of recombinant vaccine were similar to those observed after 20 micrograms doses of plasma-derived vaccine. The G.M.T. values were lowest after 2.5 micrograms doses of recombinant vaccine. However, the recipients of the 2.5 micrograms had a significant anti-HBs response after a fourth (booster) dose of recombinant vaccine was given at 12 months. A booster dose of recombinant hepatitis B vaccine was given to 31 health professionals who had been successfully immunised with plasma-derived vaccine 5-7 years previously. A significant anamnestic response was observed in 30 (97%) of these individuals in spite of the fact that 16 (52%) had low or undetectable levels of anti-HBs before the booster dose was given.