Dr. Nitin Shah
Hon. Pediatrician- UHC, LTMG Hospital, Mumbai.
Treasurer, Indian Academy of Pediatrics, 1998-2001.
1. What is the prevalence of Hepatitis - B in India?
1. India falls into intermediate category of HbsAg prevalence with a carrier rate of 4.2%, which means that there are estimated 40 million carriers in India. 60 – 70% of acute hepatitis in adults, 20 – 25% of acute hepatitis in children, 60 – 70% of chronic hepatitis, 50% of chronic liver diseases, 20 – 30% of cases of fulminant hepatitis and 80% of pediatric cases of primary liver cell carcinoma are due to HBV infection. It is estimated that 30 – 40% of the total population show some serological markers of past infection with HBV
2. What is the natural history of Hepatitis B?
2. HBV infection in < 10 year old child is mostly insidious and milder. Younger the age at which the infection occurs, milder is the clinical course, however, higher is the chance of becoming a chronic carrier. If a newborn is infected, he rarely develops acute hepatitis but has 90% chance of becoming a carrier. 25% of such newborns will develop chronic liver disease by the 3rd or 4th decade of life. Some of them will even go on to develop liver carcinoma.
Adults infected with HBV develop acute hepatitis and most of them recover. 5 – 10% develop chronic carrier state. Again of these carriers, 30% will develop chronic liver disease and some will develop carcinoma of liver. 1 – 2% of patients with HBV infection develop fulminant hepatitis which carries> 80% mortality.
3. What are the modes of transmission of HBV?
3. Vertical transmission occurs from HbsAg positive pregnant women to their babies during the perinatal period. It mainly occurs due to maternal blood infecting the baby. The efficacy of transmission is 30% if the mother is also ‘e’Ag negative and 70 – 90% if ‘e’Ag positive (10% of pregnant mothers who are HbsAg positive are also ‘e’ Ag positive in India). 30% of carrier pool is contributed by vertical route.
Horizontal transmission occurs due to close contact e.g. amongst family members or at day care centers. 50 – 70% of the carrier pool is contributed by horizontal transmission.
Parenteral route can also lead to spread via blood products, contaminated needles, surgical instruments, IV drug abuse, tattooing, acupuncture needles, ear piercing etc. Last is the sexual route of transmission, which occurs when one partner is infected.
In developed countries, sexual transmission is a common route.
4. Which vaccines are available against HBV?
4. Basically there are 2 types of vaccines. The first generation vaccine is a plasma-derived vaccine, containing purified inactivated HbsAg particles obtained from pooled plasma of healthy chronic carriers. The process of purification is so intense and stringent that all known pathogens including HIV are killed. The second-generation vaccine is a DNA recombinant vaccine where HbsAg is obtained from yeast or of late CHO cell line, using recombinant DNA technique. It is the purest vaccine ever produced.
Being dependent on constant supply of plasma of HbsAg carriers, plasma derived vaccine will have limited sources and as the demand increases we will have to rely more on the recombinant technique to produce pure HbsAg at will. Again, combination vaccines containing HbsAg and DTP will be possible using only recombinant DNA vaccine.
5.Which hepatitis B vaccine is recommended to be used?
5. Both the vaccines are equally efficacious and safe. Any one of them can be used.
6. How are these vaccines available?
6. Unit dose of both the vaccines contains 10 mcg per vial for pediatric use and 20 mcg per vial for adult use. Multidose vials of both contain 20 mcg /ml and hence 0.5 ml per dose will be used for children <10 years and 1.0 ml for children> 10 years and adults. Multidose vials are available as 5.0ml or 10.0ml bulbs.
7. What is the dose and schedule of Hepatitis B immunization?
7. Dose depends on the age of the child. For a child <10 years, 10 mcg/dose is advocated and for a child> 10 years, 20 mcg. It is given IM in the anterolateral aspect of thigh, or in the deltoid muscle in older children. Avoid using gluteal region, as the fat mass is large in that area which can lead to poor sero response.
Schedule consists of giving 3 doses at 0,1 and 6 months. It is preferable to start the vaccination as early as possible at birth, in which case the 2nd dose can be given at 6 weeks along with OPV/DPT and 3rd dose can be given at 6 months, or at 9 months along with the measles vaccine.
As routine antenatal screening for HbsAg is neither practical nor possible in our country, the first dose of vaccine should ideally be given within 12 hrs. of birth. If it is missed at birth, it should be given as early as possible and no age is late for starting vaccination.
8. What is the immune response following Hepatitis B vaccine?
8. Hepatitis B vaccine induces anti HBs antibodies, which are protective in nature. Seroconversion is defined as titres from 2-10mcg/ml whereas titres>10-100 mcg/ml are considered as seroprotective. 98-99% of vaccinees show seroconversion following 3 doses, 95% show seroprotection. 95-98% of children and adolescents show seroprotection with high titres as compared to 85-90% in those who are above 40 years of age. Seroprotective titres are achieved in 20-30% after 1st dose, in 80-90% after 2nd dose and in 95-98% after 3rd dose. The titres achieved are GMT of 100-200 after 1st dose, 300-500 after 2nd dose and 1000-10,000 after 3rd dose.
Higher the titre after the 3rd dose, longer it will last. The titres decline by 50% at 1 year after last dose and thus fall gradually over next 10-20 years. The protective titres persist in most for next 10-20 years. Hence, a booster is not required for 5-10 years.
Hepatitis B induces strong T cell response and memory. Some studies have shown that there is natural boosting in later years without getting clinical disease. Some have shown asymptomatic antiHBc conversion in vaccinees, proving asymptomatic subclinical infection. In some, anamestic response occurred following exposure to HBV later on even when the antiHBs titre had become undetectable, again indicating strong T cell memory. This is the reason why many people feel that a booster is not required in a normal person.
9. What if the child comes late for subsequent doses?
9. If the gap between the first and the second dose is less than 6 months, and that between 2nd and 3rd dose is less than 1 year, there is no need to restart the course. Instead just complete the remaining doses as per original schedule. However such delays are not desirable as the child remains unprotected till the course of 3 doses is completed.
* Hepatitis B induces strong T cell response and memory . Anamestic response occurs even when the antiHBs titre had become undetectable.Hence according to the latest data there is no need to revaccinate the child even if the gap between the first and the second dose is more than 6 months, and that between 2nd and 3rd dose is more than 1 year. Instead just complete the three doses of vaccination as the child remains unprotected till the course of 3 doses are completed .
10. What are the side effects of Hepatitis B vaccine?
10. The side effects of both the vaccines are very few if any. Local reactions including erythema, pain and swelling at injection site are seen in < 20% of cases. Systemic side effects like fever are rare. Serious complication like anaphylaxis is extremely rare and is same as with some other vaccines.
11. What about vaccine failure?
11. Vaccine failure can occur due to poor storage and poor cold chain maintenance. True vaccine failure occurs in less than 2 – 3% of vaccinees. It can be due to immune compromised state of the host like patients with leukemia, hemodialysis patients. In such cases using double the dose and additional 1 – 2 doses may help them. Yet, as low as 25 – 30% of cases of leukemia have been shown to seroconvert and they may have to be given passive prophylaxis using HBIG. Poor response is also seen in males, obese patients, diabetics, smokers, alcoholics, those>40 years old, those on long-term high dose steroids etc. Injection in gluteal region also evokes poor response.
Other reasons for vaccine failure is infection with surface mutant strains, which will escape neutralization by surface antibody and lead to infection inspite of presence of anti HbsAg antibodies. Use of pre –S containing vaccine will help against such infection. Lastly, some patients just do not respond which may be because of T cell suppression without obvious immune deficiency due to genetic variability or they may be actually harboring low grade HBV infection which goes undetected before vaccination.
12. How do you manage a newborn born to HbsAg positive mother?
12 .To protect the infant, the first dose of vaccine should be given as early as possible after birth (within 2 – 3 days, preferably within 12 hours of birth). If affordable and available, HBIG 0.5 ml should be given IM on the other thigh within 6 hours of birth (do not give HBIG and vaccine on the same thigh). It is then followed by 2 more doses of the vaccine at 1 and 6 months. One can also use accelerated schedule of 0, 1, 2 and 12 months especially if HBIG is not given.
13. What about immuno – compromised children?
13. Children with leukemia, on chemotherapy, multi – transfused thalassemics, patients on high dose long-term steroids and patients on hemodialysis have poor seroconversion following conventional schedule. Hence it is recommended to double the dose of vaccine (i.e. 20 mcg in children <10 yrs of age and 40mcg in children> 10 yrs of age). If antibody titres are not satisfactory after 3 doses, additional 1-3 doses should be given. If still there is no response one can give HBIG passive prophylaxis. If rapid response is necessary one can use 0,1,2 & 12 months schedule. Even children with Down’s syndrome show poor seroconversion & titres and should be given double the normal doses
14. Can Hepatitis B vaccine be given intradermally?
14. Advantage of using intradermal route is that only 0.1 ml dose is required bringing down the cost of vaccine by 80%. The disadvantage is that the seroconversion is not as good as with IM route and titres are not as high and may not last as long as expected. This means it will be mandatory to do antibody titres after 3 doses, which will counter the cost benefit. If the titres are low after 3 doses, a normal IM dose will be required. Considering all these factors intradermal route is not recommended.
15. What is the upper age limit for Hepatitis B vaccination?
15. As the risk of horizontal / parenteral transmission continues throughout life, no age is late for starting Hep B vaccination. Response to vaccination is low after 4th decade of life. Hence earlier the better.
16. Can plasma derived vaccine be given in 5 mcg dose to newborns?
16. There are no standard references to suggest use of 5 mcg dose of plasma derived vaccine in newborns. Hence recommended dose even in newborn is 10mcg.
17. Is Hepatitis B vaccine recommended for universal immunization?
17. In 1987, WHO recommended inclusion of Hepatitis B into national schedule. The target set was inclusion by 1997 of hepatitis B vaccine in national schedule by all the countries with>2% carrier rate and by 2000 by all the countries. The status today is that more than 90 countries have already included it in their national schedule giving the vaccine free of cost. That covers more than 50% of target population of the world. This includes predominantly the western world.
India has yet not accepted this concept. IAP and other professional similar bodies have already recommended it to be part of the national schedule. Till then, it is recommended to give it to each and every child whose parents can afford it.
17a. What is catch up vaccination?
17a. When you include hepatitis B vaccine for universal vaccination, all newborns will automatically receive it. But the older children, adolescents and adults are left behind which will be a huge number. Policy adopted to vaccinate them is called as catch up vaccination. Best policy will be to mass vaccinate all adolescents who have not been vaccinated before. When continued for 10-12 years, the entire unvaccinated cohort will get vaccinated.
17b. What is the impact of universal hepatitis B vaccination on hepatitis B?
17b. The results of universal hepatitis B vaccination will be obvious in next 5-10 years. The carrier rate fell by more than 90% within 5 years as seen in Thailand study and the incidence of hepatocellular carcinoma fell by 85% as seen in Taiwan study.
18. Should Hepatitis B vaccine be given to a carrier or to a patient who has recovered from HBV infection?
18. Neither the carrier nor the patient who has recovered needs Hepatitis B vaccine. In fact, a patient of HBV infection develops protective antibodies to surface antigen (anti – HBs) on recovery. There is no risk associated with vaccination, but it is a total waste of such an expensive vaccine.
19. Can you use different Hepatitis B vaccines interchangeably?
19. If there is no other option, yes, they can be interchanged either during primary doses or when giving boosters. However, it is not ideal or desirable to do so. With many brands coming up it is going to be practically difficult, as a patient may go to a different doctor to complete the course and may get a different vaccine.
20. Can you give Hepatitis B vaccine along with other vaccines?
20. With so many vaccines to be given in the first year of life, one has to give more than 2 vaccines on the same day to complete all the vaccination in time. First dose of Hepatitis B vaccine can be given along with OPV zero dose / BCG. 2nd dose of Hepatitis B vaccine can be given along with OPV/DPT/Hib at 6 weeks of age and 3rd dose can be given along with Measles vaccine at 9 months. The vaccines should be given on the same day but at different sites using different syringes or as combination vaccine like DPT+Hepatitis B vaccine.
21.What if the newborn is premature?
21. Newborn < 2.0 kg, will have lesser chances of seroconversion than full term child. If the mother is known to be HbsAg negative one can postpone the vaccination. But if the mother is HbsAg positive or if the status is not known, one should give first dose at birth. If mother is carrier, giving HBIG on other thigh will be mandatory. This can be followed by completion of course using 0, 1, 6 or 0, 1, 2 & 12 schedule.
22.What is cost effectiveness of universal neonatal immunization Vs selective immunization of newborns born to HbsAg positive mothers?
22. If one follows up a cohort of newborns, only 15-20% of those who become carrier by 1 year are born to HbsAg positive mothers. Rest have all acquired HbsAg horizontally through unknown sources. Hence, by selectively immunizing only babies born to carrier mother will not help majority. Besides, such selective approach will entail doing HbsAg in all the mothers before birth. This is neither practicable nor cost effective at present.
23. What is high – risk approach Vs universal immunization?
23. Universal approach means immunizing everyone in the community especially all newborns. It will entail tremendous expenditure. If that is not possible, at least persons who are at high risk for infection should be vaccinated. This includes newborns born to HbsAg positive mothers, patient needing blood or blood products, hemodialysis patient, family members of an index case or carrier, day – care centre inmates, prison inmates, health – care personnel, sex workers, IV drug abusers etc.
23a. Why not vaccinate only those at high risk for HBV infection?
23a. As discussed before, only 30% of total carrier pool is contributed by vertical route and another 25% by other known source of HBV infection. Almost 50% of carrier pool is contributed by unknown source of infection or horizontal route. Hence, if you target only high-risk people i.e. people with known risk factors for HBV, it will not prevent 50-60% of carriers. Hence, one has to vaccinate all to decrease carrier pool over 5-10 years. In USA, targeted vaccination strategy was used for 10 years but it did not work. Once it shifted to mass vaccination, it made a major dent in the carrier pool. Hence universal vaccination is the only strategy that will work.
24.What is cost effectiveness of universal approach?
24. The main problem of universal approach is the current high cost of vaccine. With 25 million children born per year in India, it will cost Rs. 400 crores annually to immunize all newborns with 3 doses. As against without vaccination there will be cost involved in treating patients with chronic liver diseases and carcinoma of liver. The benefit of universal vaccination will be evident only 10 years later when the carrier pool will start decreasing. It is estimated that for every rupee invested in vaccination today we will save Rs. 5 each year after 10 years. In any case, life can not be equated with money all the time.
25. What advances have occurred in Hepatitis B vaccine?
25. Two advances are of importance. First is the development of better immunogenic vaccine especially the one with the pre-S component and second is the combination vaccine where Hepatitis B vaccine is combined with Hepatitis–A (Twinrix vaccine) or with other vaccine like DPT, DPaT, DPT/ killed polio, DPT/ killed polio/ Hib etc. This will bring down the number of injections given to the child and may even reduce the cost.
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