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Eliminating hepatitis B virus through neonatal ... - Journal of Hepatology

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In the past decades, two effective strategies have been developed to fight against hepatitis B virus (HBV): neonatal vaccination to prevent new infection and ...
Editorial

Eliminating hepatitis B virus through neonatal vaccination: Can we make it? Chau-Ting Yeh⇑, Ming-Wei Lai Liver Research Center, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei, Taiwan

See Article, pages 515–521

In the past decades, two effective strategies have been developed to fight against hepatitis B virus (HBV): neonatal vaccination to prevent new infection and antiviral agents to treat existing chronic hepatitis B. The immunogen in the hepatitis B vaccine is derived from a recombinant HBV surface protein, which elicits generation of a protective antibody directed against the HBV surface antigen (anti-HBs). In Taiwan, following the launch of the universal hepatitis B vaccination program, the carrier rate in the vaccination era has significantly decreased from around 10% to nearly 1% [1]. Furthermore, the occurrence of hepatocellular carcinoma in children has decreased from 0.70 to 0.36 and further down to 24 h after birth may also contribute to the high infectious rate. In this study, the HBIG was given within 72 h of birth. Another concern raised by this report is that a high proportion of the infected children were tested negative for serum antibody to the HBV core antigen (anti-HBc), a marker generally used to determine whether the

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JOURNAL OF HEPATOLOGY patient has been infected by HBV. The present findings, if verified further, question the reliability of this practice in post-vaccination HBV infection. One possible explanation for this unusual observation is that the viremia was detected in an early stage of infection when the anti-HBc level remained low. A longitudinal follow-up with analysis of sequential serum samples can clarify this issue. Alternatively, false positivity of HBV DNA results due to contamination remains a concern. A major virological issue in post-vaccination HBV infection is the presence of the HBV S gene mutations in many of these patients. The mutations usually develop on or around the ‘‘a’’ determinant, resulting in reduced binding ability to anti-HBs antibodies. These ‘‘vaccine or immune escape’’ mutants can also lead to detection failure of HBsAg thus resulting in a HBsAg-negative phenotype. Although this is a plausible scenario, a great proportion of patients with post-vaccination occult HBV infection do not harbor S gene mutations on or around the ‘‘a’’ determinant, albeit remaining HBsAg-negative. It is possible that other host or viral factors leading to suppression of HBsAg secretion or production may contribute to the HBsAg negativity [15]. Alternatively, the viremia may be transient and thus the HBsAg level may be too low to be detected especially in the presence of anti-HBs antibodies. At this time, it is still unclear why some children cannot develop sufficient immunity against HBV post neonatal vaccination. Genetic variations and thus individual divergences in immune responses should play a role. On the other hand, it remains possible that post-vaccination infection can develop despite sufficient anti-HBs responses have been achieved. Some vaccine escape mutants still replicate well under a relatively high titer of anti-HBs. In view of that, it is always a viable question as to whether the immune escape mutants can spread among individuals receiving complete vaccination. In antiviral therapies, S gene mutants evolve in two ways. Firstly, the drug resistant mutants carrying the polymerase gene mutations are accompanied by the S gene mutations owing to the overlapping S and polymerase reading frames. Secondly, following clearance of HBV-DNA and HBsAg by potent antiviral therapies, anti-HBs emerges followed by selection of the S gene mutants [16,17]. These vaccine-escape-like mutants with reduced HBs antigenicity have been proposed to be a possible infectious source for postvaccination HBV infection [18]. At this time, however, only silent and transient infection by drug resistant HBV mutants has been experimentally demonstrated in vaccinated chimpanzees [19]. Identification of the post-vaccination HBV infection is important for the patients. Exacerbations of hepatitis activities have been observed in clinical conditions such as usage of immunosuppressants and chemotherapeutic agents. This could be prevented if occult HBV infection was recognized in advance. The long-term consequences of chronic infection by the S gene mutants are still unclear. However, increased oncogenicity has been demonstrated in animal models for some S gene mutants carrying stop codons [20]. Finally, the S gene mutations are usually accompanied by polymerase mutations. The effectiveness of the current antiviral strategies in these mutants thus requires further evaluation. Taken together, despite the progress made in the war against HBV, we are now facing a new challenge, where novel HBV mutants develop following effective vaccination and antiviral therapies. This could pose a health threat to the general population. The epidemiology, transmission, longterm consequence, and therapeutic strategy for these mutants remain unknown and await further investigation.

Conflict of interest The author declares that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Ni YH, Huang LM, Chang MH, Yen CJ, Lu CY, You SL, et al. Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology 2007;132:1287–1293. [2] Chang MH, You SL, Chen CJ, Liu CJ, Lee CM, Lin SM, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccines: a 20-year follow-up study. J Natl Cancer Inst 2009;101:1348. [3] Plymoth A, Viviani S, Hainaut P. Control of hepatocellular carcinoma through hepatitis B vaccination in areas of high endemicity: perspectives for global liver cancer prevention. Cancer Lett 2009;286:15–21. [4] Hsu HY, Chang MH, Liaw SH, Ni YH, Chen HL. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan. Hepatology 1999;30:1312–1317. [5] Jin OC, Ning CW, Shiuan K, Keow LG. Identification of hepatitis B surface antigen variants with alterations outside the ‘‘a’’ determinant in immunized Singapore infants. J Infect Dis 1999;179:259–263. [6] Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 2008;49:652–657. [7] Hsu HM, Chen DS, Chuang CH, Lu JC, Jwo DM, Lee CC, et al. Efficacy of a mass hepatitis B vaccination program in Taiwan. Studies on 3464 infants of hepatitis B surface antigen-carrier mothers. JAMA 1988;260:2231–2235. [8] Tsebe KV, Burnett RJ, Hlungwani NP, Sibara MM, Venter PA, Mphahlele MJ. The first five years of universal hepatitis B vaccination in South Africa: evidence for elimination of HBsAg carriage in under 5-year-olds. Vaccine 2001;19:3919–3926. [9] He C, Nomura F, Itoga S, Isobe K, Nakai T. Prevalence of vaccine-induced escape mutants of hepatitis B virus in the adult population in China: a prospective study in 176 restaurant employees. J Gastroenterol Hepatol 2001;16:1373–1377. [10] Hsu HY, Chang MH, Ni YH, Chen HL. Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan. Gut 2004;53:1499–1503. [11] Chakvetadze C, Roussin C, Roux J, Mallet V, Petinelli ME, Pol S. Efficacy of hepatitis B sero-vaccination in newborns of African HBsAg positive mothers. Vaccine 2011;29:2846–2849. [12] Mu SC, Lin YM, Jow GM, Chen BF. Occult hepatitis B virus infection in hepatitis B vaccinated children in Taiwan. J Hepatol 2009;50:264–272. [13] Xu L, Wei Y, Chen T, Lu J, Zhu CL, Ni Z, et al. Occult HBV infection in anti-HBspositive young adults after neonatal HB vaccination. Vaccine 2010;28: 5986–5992. [14] Shahmoradi S, Yahyapour Y, Mahmoodi M, Alavian SM, Fazeli Z, Jazayeri SM. High prevalence of occult hepatitis B virus infection in children born to HBsAg-positive mothers despite prophylaxis with hepatitis B vaccination and HBIG. J Hepatol 2012;57:515–521. [15] Bes M, Vargas V, Piron M, Casamitjana N, Esteban JI, Vilanova N, et al. T cell responses and viral variability in blood donation candidates with occult hepatitis B infection. J Hepatol 2012;56:765–774. [16] Hsu CW, Yeh CT, Chang ML, Liaw YF. Identification of a hepatitis B virus S gene mutant in Lamivudine-treated patients experiencing HBsAg seroclearance. Gastroenterology 2007;132:543–550. [17] Hsu CW, Yeh CT. Emergence of hepatitis B virus S gene mutants in patients experiencing hepatitis B surface antigen seroconversion after peginterferon therapy. Hepatology 2011;54:101–108. [18] Clements CJ, Coghlan B, Creati M, Locarnini S, Tedder RS, Torresi J. Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization? Bull World Health Organ 2010;88:66–73. [19] Kamili S, Sozzi V, Thompson G, Campbell K, Walker CM, Locarnini S, et al. Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model. Hepatology 2009;49:1483– 1491. [20] Lai MW, Huang SF, Hsu CW, Chang MH, Liaw YF, Yeh CT. Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy. Antivir Ther 2009;14:249–261.

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