|Year : 2004 | Volume
| Issue : 1 | Page : 34-38
Evaluation of immunogenicity and safety of Genevac B: A new recombinant hepatitis b vaccine in comparison with Engerix B and Shanvac B in healthy adults
V Vijayakumar , R Hari , R Parthiban , J Mehta , SP Thyagarajan
Department of Microbiology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai - 600 113, India
Department of Microbiology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai - 600 113, India
PURPOSE: Genevac B, a new indigenous recombinant hepatitis B vaccine was evaluated for its immunogenicity and safety in comparison with Engerix B (Smithkline Beecham Biologicals, Belgium) and Shanvac B (Shantha Biotechnics, India) in healthy adult volunteers. METHODS: While 240 study subjects were included in the Genevac B group, 80 each were the subjects for Engerix B and Shanvac B. A three dose regimen of 0,1,2 months was adopted with 20 gm dosage uniformly in all the three groups. Vaccinees were assessed during prevaccination, followup and post vaccination periods for clinical, haematological, biochemical and immunological parameters for safety and immunogenicity. RESULTS: Successful follow-up in all parameters for four months could be achieved in 92.5% (222/240) for Genevac B study subjects and the same was 85% (68/80) and 80% (64/80) for Engerix B and Shanvac B respectively. While 100% seroconversion was observed in all the three groups, the rate of seroprotectivity was 99.5% by Genevac B, 98.5% by Engerix B and 98.4% for Shanvac B. However the difference was not statistically significant (p>0.05). The GMT values of anti HBs after one month of completion of the vaccination were 735.50, 718.23 and 662.20 mIU/mL respectively. No systemic reaction was either seen or reported by the volunteers during the vaccination process of Genevac B and other two vaccines. Clinical, haematological and biochemical safety parameters remained within normal limits throughout the study period. CONCLUSION: The study confirms that Genevac B, the new recombinant Hepatitis B vaccine has the acceptable international standards of safety and immunogenicity.
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Vijayakumar V, Hari R, Parthiban R, Mehta J, Thyagarajan S P. Evaluation of immunogenicity and safety of Genevac B: A new recombinant hepatitis b vaccine in comparison with Engerix B and Shanvac B in healthy adults. Indian J Med Microbiol 2004;22:34-8
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Vijayakumar V, Hari R, Parthiban R, Mehta J, Thyagarajan S P. Evaluation of immunogenicity and safety of Genevac B: A new recombinant hepatitis b vaccine in comparison with Engerix B and Shanvac B in healthy adults. Indian J Med Microbiol [serial online] 2004 [cited 2020 Sep 24];22:34-8. Available from: http://www.ijmm.org/text.asp?2004/22/1/34/8059
Hepatitis B continues to be the most common blood borne infection in the World with the prevalence of over 350 million chronic carriers of hepatitis B virus (HBV) globally and is also the leading cause of chronic liver diseases and hepatocellular carcinoma. In India, there is an estimated pool of 42 million HBV carriers and 60-80% HBV mediated hepatocellular carcinoma., As there is no effective treatment for this disease, vaccination has proved vital for prevention and eradication of hepatitis B in developed world. The first generation hepatitis B vaccine was plasma derived and was successfully used from 1992 in several countries. Emini et al and Stephenne developed hepatitis B vaccine using recombinant DNA technology produced by Saccharomyces cereviciae into which a plasmid containing the gene for HBsAg has been inserted. Two recombinant vaccines were licensed in 1986 in the United States and were produced by Merk, Sharp and Dohme and Smithkline Biologicals. A third vaccine by Pasteur-Merieux was added up in 1992.
Efforts to indigenously manufacture recombinant hepatitis B vaccines have proliferated in several developing countries including India. Shantha Biotechnics, Hyderabad introduced the first indigenously prepared genetic recombinant hepatitis B vaccine, called Shanvac B in India. Several other manufactures in India have also successfully produced and marketed their genetic recombinant hepatitis B vaccines.
The aim of the present study was to evaluate the immunogenicity and safety of the new recombinant hepatitis B vaccine called Genevac B manufactured by Serum Institute of India, Pune, in healthy adult volunteers in comparison with Engerix B (Smithkline Beecham Biologicals, Belgium, and Shanvac B (Shantha Biotechnics, Hyderabad).
| ~ Materials and Methods|| |
The new genetic recombinant vaccine, Genevac B has used the yeast system called Hansenula polymorpha with aluminium hydroxide as adsorbent and thimerosal (1:20,000) as preservative. The vaccine in 20 µg/mL strength was provided by the manufacturers for the trial. While Engerix B used Saccharomyces cereviciae as the host system, Shanvac B utilised Pichia pestoris as the expression system, the absorbent and the preservative being the same for all the three vaccines.
A total of 400 healthy adult volunteers were recruited into the study and were allocated into three groups. Two hundred and forty for receiving Genevac B and 80 each for Engerix B and Shanvac B. All volunteers were fully informed of this open labeled clinical trial and a written consent was obtained from all. The study protocol was approved by the institutional review board of Dr ALM PGIBMS, University of Madras, and Drug Controller General of India, New Delhi.
The inclusion criteria of the volunteers into the study were healthy adults aged between 20 and 50 years of both the sexes; signed informed consent; negative for HBsAg and Anti HBs, and Anti HBc IgM, no history of Hepatitis B vaccination in the past, no evidence of skin diseases or infection at any site. The exclusion criteria of the volunteers into the study were age below 20 years and above 50 years, HBsAg test positive and/or anti HBs positive, inability to come for follow up, enrollment in another vaccination trial, active illness, known history of Hepatitis B infection/carrier state, hepatomegaly and/or splenomegaly, known allergy to aluminium, uncontrolled coagulopathy, known immunological deficiency including HIV infection, treatment with immunosuppressors including corticosteroids, previous administration of immunoglobulins and blood derived products in the last six months or planned to receive such product in the next seven months, chronic illness like epilepsy, previous history of treatment with extracted growth hormone, and evidence of skin diseases or infection at any site.
On fulfilling the inclusion criteria, all volunteers were subjected to prevaccination clinical examination, screening for HBsAg, Anti HBc IgM, and anti HBs, besides subjecting them for complete haemogram and liver function and renal function tests. The study population was vaccinated on a subsequent visit with the respective Hepatitis B vaccines in 1 mL quantities following 0,1 and 2 months schedule by intra muscular route. Volunteers of the study were reviewed one month after the first, second and the third doses. In all these regimes, the vaccinees were subjected to clinical examination, data collection and blood sample collection for haematological, biochemical and immunological studies. The clinical examination and data collection was done by using a structured proforma to analyse any vaccine associated adverse events besides concurrent infections. The haematological tests included total and differential WBC counts, total RBC count, haemoglobin profile and erythrocyte sedimentation rate. Biochemical tests for liver function were serum bilirubin (total, direct and indirect), serum transaminase (SGOT and SGPT), and serum alkaline phosphatase. The renal function test conducted were blood urea, serum creatinine and uric acid levels. All these investigations were conducted as per standard procedures using approved commercial kits on all serum samples (four samples/vaccine - prevaccination, post vaccination samples collected one month after each dose). All serum samples from the vaccinees were assayed for the quantitative levels of Anti HBs using Hepanostika anti HBs 3.0 (Belgium) commercial kits. The anti HBs standards supplied by Sanofipasteur, France, were used to develop the calibrated linear graph by the software installed in the ELISA Reader - Biotech model ELX 800.
A titer of atleast 1mIU/mL or more was interpreted as seroconversion and a titer above 10 mIU/mL was considered as seroprotection. The arithmetic values of anti HBs were converted as geometric mean titre (GMT) of anti HBs and compared for statistical significance using paired 't' test. Results were analysed statistically using appropriate methods.
| ~ Results|| |
On completion of four months, follow up was achieved in 222/240 (92.5%) adults in the Genevac B group, 68/80 (85%) in the Engerix B group and 64/80 (80%) in Shanvac B group, who were found to have received all the three doses of respective vaccine and given blood samples for all laboratory parameters in addition to periodic clinical evaluation. The dropout rates in these vaccine groups (7.5% - Genevac B, 15% - Engerix B, 20% - Shanvac B) were due to personal reasons. Analysis of physical examination for any adverse events associated with the vaccine, as enumerated in [Table - 1] revealed that pain at the site of injection and fever after the vaccine were the two symptoms that were seen almost in equal percentages in all the three groups of vaccines. Other safety parameters conducted in the study are analyzed in the [Table - 2], [Table - 3] and [Table - 4].
The haematological parameters [Table - 2] assessed before and after giving the vaccine remained essentially normal in all the three groups of vaccinees when compared with the respective prevaccination levels. Liver function tests [Table - 3] and renal function tests [Table - 4] also showed no significant changes between pre and post vaccination analysis in all the three groups. These safety parameters and the reactogenicity profile of all the three hepatitis B vaccinees analyzed in the study were with in normal limits.
The immunogenicity analysis is presented in [Table - 5]. It could be seen that the seroconversion (³1mIU/mL) on completion of the short course vaccination schedule of 0, 1 and 2 months was 100% in all the three groups of vaccinees. However, when the seroprotection rates (> 10mIU/mL) were analyzed, Genevac B induced 99.5% seroprotection as against 98.5% by Engerix B and 98.4% by Shanvac B. The anti HBs levels achieved in terms of their GMT were 735.5 mIU/mL by Genevac B, 718.23 mIU/mL by Engerix B and 662.20 mIU/mL by Shanvac B. On further analysis, the difference in anti HBs level was not statistically significant (p>0.05). [Table - 6] analyses the sex wise correlation with the anti HBs levels triggered by the three hepatitis B vaccines. While Engerix B elicited a higher GMT of Anti HBs in females (1373.3 mIU/mL) than males (484 mIU/mL), Genevac B and Shanvac B induced higher GMT of Anti HBs in males (734.3 and 842.4 mIU/mL respectively) than in females (428.8 and 443.3 mIU/mL respectively).
| ~ Discussion|| |
In 1993, WHO recommended that hepatitis B vaccination should be introduced in the expanded program of immunisation (EPI) of all countries by the year 1997., Introduction of hepatitis B vaccine into EPI has shown significant reduction in HBsAg carrier rate in Taiwan from 10% to less than 1%. In view of economic factors, India is still to include this vaccine in the EPI even though induction policy has been announced.
The seroconversion and seroprotection rates in adults, neonates and children using 0,1 and 2 or 0,1 and 6 schedules are expressed by GMT values in mIU/mL. In general, data comparing immune response according to age and sex have shown that adults over 40 years of age respond less than young adults and the GMT in females are higher than those in males although seroconversion rates are similar.,, Responders in younger age group have shown a GMT of about 1500 mIU/mL compared to 500 mIU/mL in the older age groups. Different recombinant vaccines in children have revealed that a GMT ranging from 294 - 314 mIU/mL was achieved at the fourth month, which increased more than 20 fold with a booster at twelveth month. Studies in infants and children (3 months -10 years) demonstrated that the recombinant vaccines are highly immunogenic in this age group.,,
Several studies have used the standard regime of 20µg dosage at 0,1 and 6 months in healthy adults resulting in a seroprotection rate of 96.5% at the seventh month with a GMT of 2204 mIU/mL. When the vaccine was administered as an accelerated series at 0,1 and 2 months, the seroprotection rate at the third month was 99% with the GMT of 167 mIU/mL, as shown in an earlier study with Engerix B vaccine.
In the present study, the data observed have correlated well with the earlier studies in terms of seroconversion or seroprotection rates and the GMT of Anti HBs induced after the accelerated regime., However, the immunogenicity response in females was observed to be lesser in Genevac B and Shanvac B administered study subjects while the females administered with Engerix B vaccine had developed a significantly higher GMT than the males in that group. Reason for this observation is not clear.
In 36 clinical trials involving 5071 healthy adults, children and infants, a total of 13,495 doses of Engerix B has been administered and the safety profile of the vaccines has been elaborated. The most frequently reported adverse event was injection site pain in 13% and headache in 3%. In the present study the injection site pain was 12.5 to 13.2% and fever was observed in 1.5 to 1.8% of the vaccinated individuals in all the vaccine groups. In conclusion, the accelerated administration schedule of Genevac B was well tolerated and provided comparable seroprotection levels of immunogenicity with internationally acceptable standards.
| ~ Acknowledgement|| |
The assistance extended for the conduct of this clinical trial by Serum Institute of India, Pune, is gratefully acknowledged.
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