Editorial

To have B or not to have B: Vaccine and the potential eradicationof hepatitis B

Harvey J. Alter⇑

Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health (NIH), Bethesda, MD, USA

See Article, pages 730–735

To have B or not to have B, that is the question?

Whether tis nobler in the mind to sufferThe slings and arrows of contagious fortuneOr to vaccinate against a sea of troublesAnd by opposing end them. . .

Liberally adapted from William Shakespeare

Development of a sterilizing vaccine is the ultimate strategyin the prevention of infectious diseases; treatment of establisheddisease pales by comparison in its relevance to global health.Classic examples of vaccination-related disease eradication aresmallpox and polio. Hepatitis B could follow a similar global tra-jectory given sufficient resources and the will of national healthpolicies. The study of Yin-Hsian Ni, under the leadership of DingShen Chen, in this issue of the Journal of Hepatology chronicleshow far we have come in the battle against hepatitis B. In1984, when a universal vaccination program was initiated inTaiwan, 10% of the population was hepatitis B surface antigen(HBsAg) positive whereas the current rate among 3332 subjectsin the Ni et al. study is 0.9%. Similarly, the prevalence of anti-coreantibody (anti-HBc) has declined from 28% to 7% while the prev-alence of protective surface antibody (anti-HBs) has risen from24% to 56%. Serial 5-year interval analyses have shown that thesetrends are progressive and it is anticipated that as fully vacci-nated children age and continue to dilute the HBsAg carrier pop-ulation, Taiwan will near-eradicate hepatitis B infection and serveas a world model of what can be achieved when there is anational will to face, manage and then prevent seemingly insur-mountable health issues.

The achievements in Taiwan are all the more remarkablegiven that only 50 years ago, hepatitis B was a disease by namealone. There were no diagnostic assays, no observed particles,no known sequences, no culture methods, no treatments andno effective prevention strategies. This void began to fill in theearly 060s with the serendipitous finding of a precipitin line inagar that resulted from the interaction between the serum of a

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Received 22 June 2012; accepted 28 June 2012q DOI of original article: 10.1016/j.jhep.2012.05.021.⇑ Tel.: +1 301 496 8393; fax: +1 301 402 2965.E-mail address: halter@dtm.cc.nih.gov

multiply transfused hemophiliac and that of an Australian aborig-ine. The aboriginal serum was part of a random panel that wasbeing tested for lipoprotein polymorphisms in the NIH laboratoryof Baruch Blumberg [1]. Early epidemiologic studies at NIHrevealed a strong and unexplained association of the ‘‘Australiaantigen’’ with leukemia. Subsequently, Blumberg moved to theFox Chase Cancer Center in Philadelphia where on the hypothesisthat the Australia antigen was genetically determined and had anassociation with leukemia, he and Tom London studied patientswith Down’s syndrome who were known to have an inheritedpredisposition to leukemia. An overall prevalence of 10% wasfound among Down’s patients, initially supporting the genetichypothesis [2]. However, subsequent studies of institutionalizedversus non-institutionalized Down’s patients showed that theassociation was not with the disease, but rather with conditionsof crowding and poor sanitation, providing the first clue to theinfectious origin of this aboriginal antigen. The subsequent obser-vation of antigen seroconversion in two Down’s syndromepatients and a technologist in the Blumberg lab, coincident withthe onset of hepatitis, provided the definitive link between anunexpected precipitin reaction and human disease and estab-lished the first hepatitis specific serologic assay [3]. Fred Princefurther defined the association showing that it was specific forserum and not infectious hepatitis [4]. Once a viral marker wasin place, hepatitis research became goal directed and acceleratedrapidly. Electron microscopy performed by Bayer and co-workers[5] demonstrated an abundance of spherical and tubular particlesin Australia antigen positive specimens. Subsequently, Dane inEngland [6] showed by immune-electron microscopy that thespherical and tubular particles resided in complexes with largerenveloped particles that proved to be the complete hepatitis Bvirion and became known as the Dane particle. The antigen thenwas renamed Hepatitis B Surface Antigen (HBsAg). Meanwhile,Gerin and Purcell [7] used newly developed rate zonal ultracen-trifugation to purify hepatitis B associated particles and to sortthe infectious Dane particles from non-infectious spheres andtubules. These physical separations and chimpanzee infectivitystudies [8] set the stage for subsequent commercial vaccinedevelopment by demonstrating that subunits of the virus wereimmunogenic, but not infectious. By 1976, only 9 years afterthe first report that the Australia antigen was associated with

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Editorial

hepatitis, and only 13 years after the ‘‘aboriginal antigen’’ had setthe chain in motion, Maurice Hilleman and co-workers at Merckmanufactured a subunit, plasma-derived vaccine ready for clini-cal trial. The clinical trial, conducted by the late Wolf Szmunessand Cladd Stevens, was a classic in design and implementation.It was a placebo-controlled efficacy trial in high-risk male homo-sexuals and provided unequivocal documentation of vaccine effi-cacy [9]. Indeed, among the 95% who responded to a full course ofvaccine, efficacy was 100%. Hence, by 1982, there was a licensedhepatitis B vaccine with the potential to eradicate this diseasethroughout the world. However, the vaccine was too expensivefor developing nations where the risks of hepatitis B were, andare, exceedingly high.

Taiwan became a focal point for large scale epidemiologicstudies of HBV prevalence, disease associations and prevention.Palmer Beasley and Lu-Yu Hwang conducted a massive prospec-tive study of the incidence of hepatocellular carcinoma (HCC)among HBsAg positive and HBsAg negative subjects [10]. By fol-lowing over 19,000 individuals, they showed that almost everycase of cirrhosis and HCC occurred in the HBsAg positive groupand that the relative risk of HCC was more than 200-fold greaterin HBV-infected individuals than in uninfected controls. Defini-tive epidemiologic links between HBV and HCC were also demon-strated in South Africa by Michael Kew [11]. This unequivocalassociation also suggested that the hepatitis B vaccine wouldprevent HBV-related HCC and hence represent the first cancervaccine. In a second series of studies, the Beasley team showedthat the offspring of HBsAg and HBeAg positive mothers had a90% chance of becoming chronic HBV carriers and that this riskcould be reduced to 5% when hepatitis B immune globulin (HBIG)and hepatitis B vaccine were administered sequentially immedi-ately after birth [12]. This set the stage for the administration ofan HBIG-vaccine combination to children of known HBsAgpositive mothers and ultimately to universal HBV vaccination ofall newborns in Taiwan. The sequential 5-year analyses ofuniversal HBV vaccination that was initiated in Taiwan in 1984and is reported herein by Ni et al., documents the predictedefficacy of universal vaccination in the prevention of hepatitis Binfection and its sequelae. The HBV/HBsAg carrier rate in Taiwanhas decreased ten-fold to less than 1%, not only protecting thevaccine recipients, but also preventing a huge number ofsecondary infections. Importantly, there is no trend to increasedprevalence with age indicating the prolonged protective effectof vaccine even in the absence of booster inoculations. The rateof occult HBV infection, characterized by the presence of HBVDNA in the absence of HBsAg has declined from 0.8% to 0.1%(p = 0.003) over this same study interval. Although not measuredin this study, other studies have already documented decliningrates of HCC in Taiwan since the inception of universal vaccina-tion [13].

It has been known since the original HBV vaccine trails in Tai-wan that there is a small, but finite proportion of HBV vaccinerecipients who nonetheless show serologic or molecular evi-dence of HBV infection. Since the primary mode of HBV transmis-sion in HBV endemic regions is from an HBsAg and HBeAgpositive mother to her offspring, the most likely reason for vac-cine failure is that the fetus was infected in utero and that theinfection was well established before vaccine was administered;this has suggested a strategy wherein HBsAg, and especiallyHBeAg, positive mothers would be given antiviral agents duringpregnancy. A second reason for vaccine failure could be a very

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high viral load that would overwhelm vaccine efficacy. Third, agiven individual might harbor a vaccine escape mutant. Whilethis is a serious theoretical concern, there is little scientific evi-dence that vaccine escape mutants have entered the general pop-ulation. The emergence of such mutants would presage that thevaccine would become less effective over time, but there is noevidence for loss of efficacy over the 25 year duration of the Tai-wanese study.

What then are the impediments to the global eradication ofhepatitis B infection? These impediments do not reside in the sci-entific arena. Indeed, the science of recombinant HBV vaccinedevelopment is very advanced and it is probable that future for-mulations will provide only marginal increases in efficacy,though they might provide benefit through ease of administra-tion and less frequent dosing. Further, the universal vaccinationprogram in Taiwan has not only established vaccine efficacy,but has provided proof of principle that HBV vaccine can be effec-tively administered to virtually all neonates in a given popula-tion, can markedly diminish the HBV carrier rate and can breakthe treacherous cycle of maternal–fetal transmission that perpet-uates the carrier state and recycles virus into the next generation.The concomitant of such vaccine efficacy is the prevention ofchronic hepatitis, cirrhosis and HCC, all of which have been doc-umented. With the Taiwan model in place, there is new impetusto attack the final hurdles to a global vaccination strategy,namely financial resources and the will of impoverished nationsto make this a national health priority. More progress has beenmade in this socio-economic arena than would have seemedimaginable only a decade ago. In a unique and truly remarkablecollaboration between the World Health Organization (WHO),UNICEF, the World Bank, the Bill and Melinda Gates Foundation,donor governments, developing countries, international develop-ment and finance organizations and the pharmaceutical industry,the Global Alliance for Vaccines and Immunization (GAVI) wasfounded in 1999. Statistics from WHO/GAVI indicate that eachyear 1.7 million children in developing countries die from a vac-cine-preventable disease; in dramatic and sobering mathematics,this represents one life every 20 seconds. These deaths are from avariety of vaccine preventable diseases including tuberculosis,diphtheria, tetanus, pertussis, measles, polio, pneumococcalpneumonia, and rotavirus-induced diarrhea. Deaths from hepati-tis B are less acute, but perhaps equally devastating over a life-time. GAVI has thus far fostered immunization of 326 millionchildren and has set a goal to immunize 243 million additionalchildren from 2011 to 2015 predicting this will prevent 4 millionfuture deaths. 65 countries have now introduced a pentavalentvaccine that protects against diphtheria, tetanus, pertussis, hepa-titis B, and hemophilus influenza. Hence it is apparent that hep-atitis B vaccination can be applied on a global scale and canachieve efficacy in developing countries that are willing to part-ner with GAVI to protect their populations from infant andlong-term mortality. The complete eradication of hepatitis B willtake several more generations but all the pieces are in place andthe unimaginable is now the conceivable.

Conflict of interest

The author declared that he does not have anything to discloseregarding funding or conflict of interest with respect to thismanuscript.

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References

[1] Blumberg BS, Alter HJ, Visnich S. A ‘new’ antigen in leukemia sera. JAMA1965;191:541–546.

[2] Sutnick AI, London WT, Blumberg BS. Australia antigen, Down’s syndromeand hepatitis. J Clin Invest 1967;46:1122.

[3] London WT, Sutnick AI, Blumberg BS. Australia antigen and acute viralhepatitis. Ann Intern Med 1969;70:55.

[4] Prince AM. An antigen detected in the blood during the incubation period ofserum hepatitis. Proc Natl Acad Sci U S A 1968:814–821.

[5] Bayer ME, Blumberg BS, Weiner B. Particles associated with Australia antigenin the sera of patients with leukemia, Down’s syndrome and hepatitis.Nature 1968;218:1057.

[6] Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patientswith Australia-antigen-associated hepatitis. Lancet 1970;1:695–698.

[7] Gerin J, Holland PV, Purcell RH. Australia antigen: large scale purificationfrom human serum and biochemical studies of its proteins. J Virol1971;7:569.

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[8] Buynak EB, Roehm RR, Tytell AA, et al. Development and chimpanzee testingof a vaccine against human hepatitis B. Proc Soc Exp Biol Med 1976;151:694.

[9] Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demonstrationof efficacy in a controlled clinical trial in a high risk population in the UnitedStates. N Engl J Med 1980;303:1481.

[10] Beasley RP, Hwang LY, Lin CC, et al. Hepatocellular carcinoma and HBV: aprospective study of 22,707 men in Taiwan. Lancet 1981;2:1124.

[11] Kew MC, Rossouw E, Hodkinson J, et al. Hepatitis B virus status of SouthAfrican blacks with hepatocellular carcinoma: comparison between ruraland urban patients. Hepatology 1983;3:65.

[12] Beasley RP, Hwang LW, Lee GC, et al. Prevention of perinatally transmittedhepatitis B virus infection with hepatitis B immune globulin and hepatitis Bvaccine. Lancet 1983;2:1099.

[13] Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellularcarcinoma in hepatitis B vaccines: a 20-year follow-up study. J Natl CancerInst 2009;101:1348–1355.

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