HBIG is prepared from the pooled plasma of donors who have high levels of anti-HBs. During the process of extraction for anti-HBs, viruses are inactivated, and solvents used in the preparation are removed. It excluded the products tested positive for HBsAg, anti-HCV, and HIV. It is used for post-exposure prophylaxis (passive immunoprophylaxis) of HBV infection.

HBIG was given immediately after birth to infants of HBeAg-positive HBsAg carrier mothers. In comparison to the 91 % of HBsAg carrier rate among infants without immunoprophylaxis, the HBsAg carrier rate was 26 % among infants who received three doses of HBIG at birth, 3 and 6 months old, and was 54 % in those who received a single 1.0 ml dose of HBIG at birth. The prevention efficacy was 45 % by one dose of 1.0 ml HBIG and 75 % by three doses of HBIG, respectively [14].

Currently, there are two kinds o f HBV vaccine on the market, the plasma-derived vaccine and the recombinant vaccine. The first HBsAg-based highly purified and inactivated vaccine was made by Dr. Maurice Hilleman from chronic HBV infected subject’ serum [15]. In order to produce a safe vaccine, stringent treatments with pepsin, urea, and formaldehyde and rigorous filtration to destroy all viruses, and chimpanzees test was conducted [16]. The plasma vaccine was approved by FDA of the USA in 1981 [17]. By inserting the gene coding for HBsAg, HBsAg was expressed in yeast to develop the recombinant HBV vaccine [18] and was licensed in 1986 [19]. Gradually, recombinant vaccine replaced plasma vaccine, and becomes the main vaccine used worldwide.

Active immunization with three or four doses of HBV vaccine without HBIG was proved to be immunogenic in more than 90 % of infants of non-carrier mothers or HBeAg-negative carrier mothers. Pilot clinical trial revealed that for infants of HBsAg negative mothers, the first dose of vaccine at 1 week stimulated anti-HBs within 1 month in 48 % of the neonates, and in 91 % at 2 months after the second dose. By the age of 6 months and 7 months, 96 % and 100 % vaccinees developed anti-HBs after a third dose, respectively [20].

For infants of HBeAg and HBsAg seropositive mothers , 23 % was HBsAg(+) after three doses of HBV plasma vaccine given at 1 week, 1 month, and 6 months of age, while the HBsAg positive rate was 88 % in the unvaccinated infants. The prevention efficacy of using HBV vaccines was around 75 % (Beasley RP, et al. Unpublished data).

Clinical trial combining HBIG immediately after birth followed by HBV vaccination for infants of HBeAg positive, HBsAg carrier mothers was conducted in Taiwan. The prevention efficacy was 94 %, which is superior to HBIG alone (71 %) or vaccination alone (74 %) [21, 22]. This best result of HBV prevention against perinatal transmission of HBV infection by highly infectious mothers established the ground of the later universal HBV immunization strategies and program used currently. A subsequent study using HBIG at birth and three 5-μg doses of recombinant HBV vaccine, only 4.8 % of the high risk infants became chronic carriers, with a >90 % level of protection and a rate comparable with that seen with HBIG and plasma derived hepatitis B vacc ine [23]

The world’s first universal hepatitis B vaccination program was implemented in Taiwan using strategy 1 since July 1984. Screening for maternal serum HBsAg and HBeAg during pregnancy is conducted. Infants of highly infectious mothers with positive serum HBeAg and HBsAg received HBIG within 24 h after birth in addition to three or four doses of HBV vaccine during infancy. Infants of mothers with negative HBsAg, or positive HBsAg but negative HBeAg, or unknown HBV status received three or four doses of HBV vaccine only. The coverage rate of hepatitis B vaccine for neonates is around 94–99 % [27].

In countries with low prevalence of HBV infection and better resources, HBIG is given to newborns of all HBsAg-positive mothers regardless of their HBeAg status, and three doses of HBV vaccine are given to all infants.

Since 1988, the Advisory Committee on Immunization Practices (ACIP), USA has recommended universal screening of pregnant women for HBsAg during the early prenatal period in each pregnancy. All infants should receive HBV vaccination. Infants of HBsAg seropositive mothers should receive appropriate immunization with HBIG and HBV vaccine to prevent perinatal transmission [24]. Although this strategy can save the cost of maternal screening for HBeAg, the wider use of HBIG in infants of HBsAg mothers regardless of maternal HBeAg status increases the cost.

Using three or four doses of HBV vaccine to all infants without screening maternal HBV markers is a common practice of universal immunization program in the world. It can save the cost not only for maternal screening of HBV markers, but also the cost of HBIG. This policy is practically applicable in countries with limited resources. The results of prevention is good according the report of studies in Thailand and other countries [28].

In many endemic countries with limited resources, three doses of hepatitis B vaccine are given to all infants, regardless of the HBeAg status in HBsAg carrier mothers. This strategy offers an efficacy of around 75–80 % for infants of HBeAg-positive highly infectious mothers. Nevertheless, the cost of maternal screening and subsequent use of HBIG in the newborns can be avoided.

In 1992, the World Health Assembly passed a resolution to recommend global vaccination against hepatitis B. In 2009 WHO recommended that all infants receive the  hepatitis B vaccine as soon as possible after birth, preferably within 24 h. The birth dose should be followed by two or three doses to complete the primary series.

Hepatitis B vaccine for infants was introduced nationwide in 183 countries by the end of 2013. Global coverage of infants with three doses of HBV vaccine in 1990 was only 1 %. It is gradually increased and was estimated to be as high as 81 % in 2013. A birth dose for hepatitis B vaccine was advocated by WHO, and was introduced in 93 countries by 2013, with a global coverage rate estimated as 38 %, reaching 79 % in the Western Pacific, but only 11 % in the African Region (WHO, Global immunization data) (http://​www.​who.​immunization/​monitoring_​surveillance/​data/​en/​).

Universal HBV immunization program has reduced the incidences of acute hepatitis B [31, 32]. After 25 years of un iversal HBV immunization in Taiwan, acute hepatitis B among adolescents and young adults ≤25 years old was reduced, making infants and the unvaccinated 25–39-year-old cohort additional targets for preventing acute hepatitis B (Fig. 19.2a). Vaccinated infants (0.78/100,000) had higher rates than those aged 1–14 years (0.04/100,000), due to breakthrough HBV infection from mother-to-infant transmission [32].

The mortality  rate of fulminant hepatitis per 10 ⁵  infants was reduced significantly from 5.1 in those who were born before the HBV vaccination program (1975–1984) to 1.71 in those born after the vaccination program in Taiwan (1985–1998) [33] (Fig. 19.2b ). The mortality in vaccinated birth cohorts decreased further by more than 90 % from 1977–1980 to 2009–2011 [34].

After universal HBV vaccination in Taiwan, HBV was found to very rarely cause fulminant hepatitis in children age ≥1 year, but remained a significant cause of fulminant hepatitis in infants [35]. The incidence rate ratio of patients age <1 year to those ages 1–15 years was 54.2 for HBV-positive fulminant hepatitis. HBV-positive fulminant hepatitis was prone to develop in infants born to HBeAg-negative, HBsAg-carrier mothers; these infants had not received HBIG according to the vaccination program in place. Maternal HBsAg was found to be positive in 97 % of the infants with fulminant hepatitis B, and maternal HBeAg was found to be negative in 84 % of these infants.

Universal hepatitis B vaccination programs have effectively reduced the chronic HBV infection rate in many endemic countries. The protective efficacy of the hepatitis B vaccination program in infants born to highly infectious mothers and received HBIG and vaccine on schedule was approximately 85–90 %. The early mass survey data after the universal HBV vaccination pro gram in Taiwan revealed that the protective efficacy was 86 % in the HBIG plus HBV vaccine group and 78 % in those with only three doses of HBV vaccine alone [36].

The HBsAg seropositive rates declined to below 1 % in most countries where universal vaccination programs have been successfully conducted [37]. Serial sero-epidemiologic studies started just before the universal vaccination program and every 5 years in the post-vaccination era in Taiwan in the past three decades [38–42]. The results revealed that HBsAg seroprevalence rate among children declined from 9.8 % before the HBV immunization program to 0.5–1.2 % after the program. It implicates that Taiwan has been changed from an HBV endemic country to a low endemic country by the HBV immunization program (Fig. 19.3). The HBV infection rate (anti-HBc seropositive rate) declined from 38 to 16 % and further to 4.6 % in children 15–20 years after the HBV immunization program in Taiwan [42] (Fig. 19.3). Twelve years after integration of universal hepatitis B vaccine into the national expanded program on immunization (1992) in Thailand, the HBsAg and anti-HBc seropositive rate was reduced from 4.3 % and 15.8 % among those born before the program, to 0.7 % and 2.9 % among 6 months to 18 years old born after, respectively [28].

In Gambia, villages with good HBV immunization program, vaccine efficacies in 1993 against HBV infection and chronic HBsAg carriage were 94.7 % and 95.3 %, respectively [43]. During 1986–1990, the Gambia Hepatitis Intervention Study (GHIS) comparing fully vaccinated vs. unvaccinated GHIS participants among the allocated 125,000 infants. HBV infection was 0.8 % (2/255) vs. 12.4 % (59/475), suggesting a vaccine efficacy of 94 % [44]. Study in Gambia also showed a lower anti-HBc positive rate of 27.4 % (70/255) among vaccinated participants in comparison to 56.0 % (267/475) among the unvaccinated subjects.