Brief Reports

Indian Pediatrics 2000;37: 75-80

Immunogenicity of Indigenous Recombinant Hepatitis B Vaccine in Infants Following a  0, 1, 2-Month Vaccination Schedule

From the Departments of Child Health and Clinical Virology*, Christian Medical College and Hospital, Vellore 632 004, Tamil Nadu, India.
Reprint requests: Dr. Thomas Cherian, Department of Child Health, Christian Medical College and Hospital, Vellore 632 004, Tamil Nadu, India. E-mail: [email protected]
Manuscript received: May 5, 1999;
Initial review completed: June 11, 1999;
Revision accepted: July 29, 1999

Hepatitis B virus (HBV) is a major cause of morbidity and mortality worldwide. The hepatitis B carriage rate in India ranges from 3 to 5%, placing it in the intermediate range of endemicity(1,2). About 25% of carriers will die from chronic active hepatitis, cirrhosis or primary liver cancer. Younger individuals who become infected are more likely to become chronic carriers and develop fatal complications during adulthood. In endemic areas most chronic carriers acquire infection during infancy or childhood. Hence, immunization of infants and children is the most effective tool in preventing the transmission of HBV.

In 1991, the EPI Global Advisory Group of the WHO recommended that HBV vaccination should be integrated into the national immuniza-tion programs of all countries with HbsAg carrier prevalence of 8% or higher by 1995 and in all remaining countries by 1997(3). One of the factors that have hindered the introduction of HBV vaccine in the national immunization program in India has been the high cost of the vaccine, which was imported from overseas. Recombinant HBV vaccines are now being manufactured in India and is available at nearly half the cost of the imported vaccine. However, only limited data are available on the immuno-genicity and safety of such vaccines in children. This study was conducted to determine the immunogenicity and safety of one such indi-genously manufactured recombinant hepatitis B vaccine (Shanvac^TM B) in infants.

Subjects and Methods

Healthy infants, 6-9 weeks of age, attending the well baby clinic for the first dose of DPT vaccine were recruited into the study after obtaining signed informed consent from the parent or guardian. All children had a baseline physical examination, including recording of anthropometric data such as weight, height and head circumference.

The following were excluded from the study: (i) Infants who had received hepatitis B vaccine or immune globulin at birth; (ii) Infants, who had received blood, blood products or immunoglobulin or who were likely to receive them during the period of the study; (iii) Infants born to HIV-infected mothers; (iv) Infants with suspected or proven congenital immuno-deficiency disorders; (v) Infants on immune-suppressive therapy; (vi) Infants who had participated in any other clinical trial 30 days before or during the period of this study; and (vii) Infants with hypersensitivity to yeast (infants who experienced hypersensitivity reaction after hepatitis B vaccine did not receive further doses of the vaccine).

The hepatitis B vaccine was administered at a dose of 10 micrograms intramuscularly on the right anterolateral thigh. DPT vaccine was administered in the left thigh. The second and third doses of vaccine were administered at 1-month intervals, along with the second and third doses of DPT and OPV.

The parents were given a card in which they recorded systemic and local adverse reactions such as fever, local pain, redness and irritability. The parents were also asked to grade the reactions as mild, moderate and severe. In children who received both hepatitis B vaccine and DPT vaccine, local reaction of each thigh were noted (right thigh for hepatitis B vaccine and left for DPT vaccine). To determine the systemic adverse reactions over and above that caused by DPT vaccine, 70 children who received DPT vaccine without concomitant hepatitis B vaccine were also followed up for systemic adverse reactions using the same patient diary.

Blood was collected by venipuncture before the first dose and 4 weeks after the third dose of the vaccine. The sera were separated and stored at -20�C until they were tested. The pre-immunization blood was tested for the presence of HBsAg, anti-HBc and anti-HBs using the Auszyme (Abbott Laboratories, USA), Core Abbott IMx (Abbott Laboratories, USA) and Ausab, Abbott IMx (Abbott Laboatories, USA) test kits, respectively, following the manufac-turer's instructions. Post-immunization sera were tested for the presence and titer of anti-HBs. When the titer of the neat serum sample was >1000 mIU/ml, the sera were tested after diluting the sample 1:50 in human sera negative for anti-HBs and HBsAg. Seroprotection was defined as the presence of post-immunization anti-HBs titer � 10 mIU/ml. The seroprotection rate was defined as the proportion of sero-negative subjects who developed a post-immunization antibody titer of >10 mIU/ml. The anti-HBs concentrations were log trans-formed to calculated the geometric mean.

Results

Sixty-nine infants were included in the study. Of these, sufficient pre- and post-immunization sera for all serological markers were available from 48 infants who completed all 3 doses of vaccination, as per the schedule. They included 40 infants whose pre-immuniza-tion sera were negative for all hepatitis B markers. The mean age of these infants at enrollment was 6.4 weeks (range 6-9 weeks). All 40 infants had protective antibody levels (>100 mIU/ml) in the post-immunization samples (seroprotection rate 100%, 95% CI 89.1-100%). Antibody titers were >5000 mIU/ml in 10 (25%) children, 1001-5000 mIU/ml in 26 (65%) and 101-1000 mIU/ml in 4 (10%) children, respectively. The geometric mean concentration of antibody was 2643 mIU/ml. Post immunization sera were also available from 8 infants with at least one detectable HBV marker in the pre-sera. These included one infant with anti-HBc, 2 with anti-HBs and 5 with both anti-HBs and anti-HBc. All had a significant rise in antibody levels after vaccination; 5 had antibody levels > 1000 mIU/ml, while the remaining 3 had levels (mIU/ml) of 562, 794 and 708, respectively.

None of the infants had any serious adverse event that required discontinuation of the vaccination series. The solicited local adverse events to hepatitis B and DPT vaccine, recorded by the parent in the subject diary, are shown in Table I. The commonest local adverse reaction was tenderness at the injection site and was seen in 18% and 42% of infants following the first and third dose of hepatitis B vaccine, respectively. These rates were not significantly more than local reactions following DPT vaccine (p > 0.1).

Table I^__Local Adverse Events Following Hepatitis B Vaccine and DPT Vaccine

The solicited systemic adverse events, recorded by the parents, are shown in Table II. Fever was reported in 21 to 43% of infants. Since all these infants received DPT vaccine concomitantly, we also studied the systemic adverse events following DPT vaccine alone. The systemic adverse events following hepatitis B vaccine plus DPT vaccine were not signifi-cantly more than DPT vaccine alone (p >0.1).

Table II^__ Systemic Adverse Events in Children Receiving DPT and Hepatitis B Vaccine (HBV) or DPT Vaccine Alone

Discussion

In this study we found that the indigenously prepared recombinant hepatitis B vaccine was highly immunogenic with 100% seroprotection (95% CI 89-100%). The Geometric Mean Titre (GMT) of Anti-HBs following 3 doses of vac-cine using a 0, 1, 2-month schedule, starting at 6 weeks of age, was 2643 mIU/ml. We opted to use this schedule so that the vaccine could be administered at the same time as the routine EPI vaccines and an extra immunization visit at 6 months could be avoided.

The results of similar studies using different foreign-made vaccines using different schedules and dosages as well as the results of this study are shown in Table III. The seroconversion rates in our study were comparable to that with other vaccines(4-8). Though the GMT of post- vaccination antibody was lower than the GMT following 0, 1, 6-months vaccination sche-dule(4,5), it was higher than the GMT following the 2, 4, 6-months schedule using other vac-cines(7,8). However, since the vaccination sche-dule, the study population and the laboratory where antibody tests were done vary between the studies, direct comparison of the results of this study with that of other studies may not be appropriate. A randomized-controlled trial would be required to determine, whether this vaccine is superior to other vaccines. However, the present study has established that the vaccine is highly immunogenic and produces high antibody levels in children even when it is administered along with DPT and OPV at 6, 10 and 14 weeks of age.

Table III^__Comparison of Immune Responses of Infants to Various Recombinant Hepatitis B Vaccines

In our study, good antibody response was seen even in the 8 children who had pre-existing antibodies to HBV (probably maternally acquired), suggesting that immune response to vaccination was not significantly altered by pre-existing antibodies. One child with pre-existing anti-HBc but negative anti-HBs (suggesting that the mother may have been a carrier) had high level of anti-HBs post vaccination. This suggested that the child was not chronically infected and had protective antibody level following vaccination.

Most of infants tolerated the vaccine very well and no serious adverse events were noted. In local reactions, tenderness at injection site of hepatitis B vaccination was found in a signifi-cant number of children following 1st and 3rd dose. There were no marked difference in sys-temic adverse events between children who received DPT vaccine alone or DPT and hepatitis B vaccine.

Acknowledgements

This study was supported by a grant from Shantha Biotechnics, Private Ltd., Hyderabad, India. The authors would like to acknowledge the assistance of the medical officers and the nurses in the Well Baby clinic in the conduct of this study.

References

1. Tandon BN. Dimensions and issues of HBV control in India. In: Hepatitis B in India: Problems and Prevention. Eds. Sarin SK, Singhal AK. New Delhi, CBS publishers and Distributors; 1996; pp 1-4.

2. Nayak NC, Panda SK, Zuckerman AJ, Bhan MK, Guha DK. Dynamics and impact of perinatal transmission of HBV in North India. J Med Virol 1987; 21: 137-145.

3. World Health Organization. Hepatitis B vaccine - making global progress. EPI Update, October 1996.

4. Goldfarb J, Baley J, Medendorp SV, Seto D, Garcia H, Toy P, et al. Comparative study of immunogenicity and safety of two dosing schedules of Recombinant DNA vaccine in neonates. Pediatr Infect Dis J 1994; 13: 18-22.

5. Goldfarb J, Medendorp SV, Nagamori K, Buscarino C, Krause D. Comparison study of the immunogenicity and safety of 5 microgram and 10 microgram dosages of recombinant hepatitis B vaccine in healthy children. Pediatr Infect Dis J 1996; 15: 768-771.

6. Keyserling HL, West DJ, Hesley TM, Bosley C, Wiens BL, Calandra GB. Antibody responses of healthy infants to a recombinant hepatitis B vaccine administered at two, four and twelve or fifteen months of age. J Pediatr 1994; 125: 67-69.

7. Goldfarb J, Medendorp SV, Garcia H, Nagamori K, Rathfon H, Krause D. Comparison study of the immunogenicity and safety of 5-and 10 mg dosages of a recombinant hepatitis B vaccine in healthy infants. Pediatr Infect Dis J 1996; 15: 764-767.

8. Greenberg DP, Vadheim CM, Wong VK, Marcy SM, Partridge S, Greene T, et al. Comparative safety and immunogenicity of two recombinant hepatitis B vaccines given to infants at two, four and six months of age. Pediatr Infect Dis J 1996; 15: 590-596.

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