Journal of Hepatology
Volume 57, Issue 4 , Pages 715-717, October 2012
Harvey J. Alter
Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health (NIH), Bethesda, MD, USA
Received 22 June 2012; accepted 28 June 2012. published online 04 July 2012.
See Article, pages 730–735
To have B or not to have B, that is the question?
Whether tis nobler in the mind to suffer
The slings and arrows of contagious fortune
Or to vaccinate against a sea of troubles
And by opposing end them…
Liberally adapted from William Shakespeare
Development of a sterilizing vaccine is the ultimate strategy in the prevention of infectious diseases; treatment of established disease pales by comparison in its relevance to global health. Classic examples of vaccination-related disease eradication are smallpox and polio. Hepatitis B could follow a similar global trajectory given sufficient resources and the will of national health policies. The study of Yin-Hsian Ni, under the leadership of Ding Shen Chen, in this issue of the Journal of Hepatology chronicles how far we have come in the battle against hepatitis B. In 1984, when a universal vaccination program was initiated in Taiwan, 10% of the population was hepatitis B surface antigen (HBsAg) positive whereas the current rate among 3332 subjects in the Ni et al. study is 0.9%. Similarly, the prevalence of anti-core antibody (anti-HBc) has declined from 28% to 7% while the prevalence of protective surface antibody (anti-HBs) has risen from 24% to 56%. Serial 5-year interval analyses have shown that these trends are progressive and it is anticipated that as fully vaccinated children age and continue to dilute the HBsAg carrier population, Taiwan will near-eradicate hepatitis B infection and serve as a world model of what can be achieved when there is a national will to face, manage and then prevent seemingly insurmountable health issues.
The achievements in Taiwan are all the more remarkable given that only 50
years ago, hepatitis B was a disease by name alone. There were no diagnostic assays, no observed particles, no known sequences, no culture methods, no treatments and no effective prevention strategies. This void began to fill in the early ′60s with the serendipitous finding of a precipitin line in agar that resulted from the interaction between the serum of a multiply transfused hemophiliac and that of an Australian aborigine. The aboriginal serum was part of a random panel that was being tested for lipoprotein polymorphisms in the NIH laboratory of Baruch Blumberg [1]. Early epidemiologic studies at NIH revealed a strong and unexplained association of the “Australia antigen” with leukemia. Subsequently, Blumberg moved to the Fox Chase Cancer Center in Philadelphia where on the hypothesis that the Australia antigen was genetically determined and had an association with leukemia, he and Tom London studied patients with Down’s syndrome who were known to have an inherited predisposition to leukemia. An overall prevalence of 10% was found among Down’s patients, initially supporting the genetic hypothesis [2]. However, subsequent studies of institutionalized versus non-institutionalized Down’s patients showed that the association was not with the disease, but rather with conditions of crowding and poor sanitation, providing the first clue to the infectious origin of this aboriginal antigen. The subsequent observation of antigen seroconversion in two Down’s syndrome patients and a technologist in the Blumberg lab, coincident with the onset of hepatitis, provided the definitive link between an unexpected precipitin reaction and human disease and established the first hepatitis specific serologic assay [3]. Fred Prince further defined the association showing that it was specific for serum and not infectious hepatitis [4]. Once a viral marker was in place, hepatitis research became goal directed and accelerated rapidly. Electron microscopy performed by Bayer and co-workers [5] demonstrated an abundance of spherical and tubular particles in Australia antigen positive specimens. Subsequently, Dane in England [6] showed by immune-electron microscopy that the spherical and tubular particles resided in complexes with larger enveloped particles that proved to be the complete hepatitis B virion and became known as the Dane particle. The antigen then was renamed Hepatitis B Surface Antigen (HBsAg). Meanwhile, Gerin and Purcell [7] used newly developed rate zonal ultracentrifugation to purify hepatitis B associated particles and to sort the infectious Dane particles from non-infectious spheres and tubules. These physical separations and chimpanzee infectivity studies [8] set the stage for subsequent commercial vaccine development by demonstrating that subunits of the virus were immunogenic, but not infectious. By 1976, only 9years after the first report that the Australia antigen was associated with hepatitis, and only 13years after the “aboriginal antigen” had set the chain in motion, Maurice Hilleman and co-workers at Merck manufactured a subunit, plasma-derived vaccine ready for clinical trial. The clinical trial, conducted by the late Wolf Szmuness and Cladd Stevens, was a classic in design and implementation. It was a placebo-controlled efficacy trial in high-risk male homosexuals and provided unequivocal documentation of vaccine efficacy [9]. Indeed, among the 95% who responded to a full course of vaccine, efficacy was 100%. Hence, by 1982, there was a licensed hepatitis B vaccine with the potential to eradicate this disease throughout the world. However, the vaccine was too expensive for developing nations where the risks of hepatitis B were, and are, exceedingly high.
Taiwan became a focal point for large scale epidemiologic studies of HBV prevalence, disease associations and prevention. Palmer Beasley and Lu-Yu Hwang conducted a massive prospective study of the incidence of hepatocellular carcinoma (HCC) among HBsAg positive and HBsAg negative subjects [10]. By following over 19,000 individuals, they showed that almost every case of cirrhosis and HCC occurred in the HBsAg positive group and that the relative risk of HCC was more than 200-fold greater in HBV-infected individuals than in uninfected controls. Definitive epidemiologic links between HBV and HCC were also demonstrated in South Africa by Michael Kew [11]. This unequivocal association also suggested that the hepatitis B vaccine would prevent HBV-related HCC and hence represent the first cancer vaccine. In a second series of studies, the Beasley team showed that the offspring of HBsAg and HBeAg positive mothers had a 90% chance of becoming chronic HBV carriers and that this risk could be reduced to 5% when hepatitis B immune globulin (HBIG) and hepatitis B vaccine were administered sequentially immediately after birth [12]. This set the stage for the administration of an HBIG-vaccine combination to children of known HBsAg positive mothers and ultimately to universal HBV vaccination of all newborns in Taiwan. The sequential 5-year analyses of universal HBV vaccination that was initiated in Taiwan in 1984 and is reported herein by Ni et al., documents the predicted efficacy of universal vaccination in the prevention of hepatitis B infection and its sequelae. The HBV/HBsAg carrier rate in Taiwan has decreased ten-fold to less than 1%, not only protecting the vaccine recipients, but also preventing a huge number of secondary infections. Importantly, there is no trend to increased prevalence with age indicating the prolonged protective effect of vaccine even in the absence of booster inoculations. The rate of occult HBV infection, characterized by the presence of HBV DNA in the absence of HBsAg has declined from 0.8% to 0.1% (p=0.003) over this same study interval. Although not measured in this study, other studies have already documented declining rates of HCC in Taiwan since the inception of universal vaccination [13].
It has been known since the original HBV vaccine trails in Taiwan that there is a small, but finite proportion of HBV vaccine recipients who nonetheless show serologic or molecular evidence of HBV infection. Since the primary mode of HBV transmission in HBV endemic regions is from an HBsAg and HBeAg positive mother to her offspring, the most likely reason for vaccine failure is that the fetus was infected in utero and that the infection was well established before vaccine was administered; this has suggested a strategy wherein HBsAg, and especially HBeAg, positive mothers would be given antiviral agents during pregnancy. A second reason for vaccine failure could be a very high viral load that would overwhelm vaccine efficacy. Third, a given individual might harbor a vaccine escape mutant. While this is a serious theoretical concern, there is little scientific evidence that vaccine escape mutants have entered the general population. The emergence of such mutants would presage that the vaccine would become less effective over time, but there is no evidence for loss of efficacy over the 25year duration of the Taiwanese study.
What then are the impediments to the global eradication of hepatitis B infection? These impediments do not reside in the scientific arena. Indeed, the science of recombinant HBV vaccine development is very advanced and it is probable that future formulations will provide only marginal increases in efficacy, though they might provide benefit through ease of administration and less frequent dosing. Further, the universal vaccination program in Taiwan has not only established vaccine efficacy, but has provided proof of principle that HBV vaccine can be effectively administered to virtually all neonates in a given population, can markedly diminish the HBV carrier rate and can break the treacherous cycle of maternal–fetal transmission that perpetuates the carrier state and recycles virus into the next generation. The concomitant of such vaccine efficacy is the prevention of chronic hepatitis, cirrhosis and HCC, all of which have been documented. With the Taiwan model in place, there is new impetus to attack the final hurdles to a global vaccination strategy, namely financial resources and the will of impoverished nations to make this a national health priority. More progress has been made in this socio-economic arena than would have seemed imaginable only a decade ago. In a unique and truly remarkable collaboration between the World Health Organization (WHO), UNICEF, the World Bank, the Bill and Melinda Gates Foundation, donor governments, developing countries, international development and finance organizations and the pharmaceutical industry, the Global Alliance for Vaccines and Immunization (GAVI) was founded in 1999. Statistics from WHO/GAVI indicate that each year 1.7 million children in developing countries die from a vaccine-preventable disease; in dramatic and sobering mathematics, this represents one life every 20seconds. These deaths are from a variety of vaccine preventable diseases including tuberculosis, diphtheria, tetanus, pertussis, measles, polio, pneumococcal pneumonia, and rotavirus-induced diarrhea. Deaths from hepatitis B are less acute, but perhaps equally devastating over a lifetime. GAVI has thus far fostered immunization of 326 million children and has set a goal to immunize 243 million additional children from 2011 to 2015 predicting this will prevent 4 million future deaths. 65 countries have now introduced a pentavalent vaccine that protects against diphtheria, tetanus, pertussis, hepatitis B, and hemophilus influenza. Hence it is apparent that hepatitis B vaccination can be applied on a global scale and can achieve efficacy in developing countries that are willing to partner with GAVI to protect their populations from infant and long-term mortality. The complete eradication of hepatitis B will take several more generations but all the pieces are in place and the unimaginable is now the conceivable.
Conflict of interest
The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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