Eliminating hepatitis B virus through neonatal vaccination: Can we make it?
Authors: Chau-Ting Yeh, Ming-Wei Lai
Journal: Journal of Hepatology (2012)

High prevalence of occult hepatitis B virus infection in children born to HBsAg-positive mothers despite prophylaxis with hepatitis B vaccination and HBIGJournal of HepatologyVol. 57Issue 3PreviewOccult hepatitis B virus (HBV) infection is a well-recognized clinical entity characterized by the detection of HBV DNA in serum and/or liver in the absence of detectable hepatitis B surface antigen (HBsAg). The frequency of the diagnosis depends on the relative sensitivity of both HBsAg and HBV DNA assays. We aimed at determining the prevalence of occult HBV infection in a high risk group of children who developed HBV infection despite immunoprophylaxis. Full-Text PDF 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]Ni Y.H. Huang L.M. Chang M.H. Yen C.J. Lu C.Y. You S.L. et al.Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.Gastroenterology. 2007; 132: 1287-1293Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar]. Furthermore, the occurrence of hepatocellular carcinoma in children has decreased from 0.70 to 0.36 and further down to <0.2 per 100,000, in 10 and 20 years following the campaign [[2]Chang M.H. You S.L. Chen C.J. Liu C.J. Lee C.M. Lin S.M. et al.Decreased incidence of hepatocellular carcinoma in hepatitis B vaccines: a 20-year follow-up study.J Natl Cancer Inst. 2009; 101: 1348Crossref PubMed Scopus (448) Google Scholar]. Similar results have been observed in other parts of the world [[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: 15-21Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. On the other hand, oral antiviral agents functioning as potent inhibitors of the HBV reverse transcriptase have proven to be successful in suppressing HBV replication and thus halting the progression of chronic liver diseases. Furthermore, pegylated interferon therapy could lead to seroclearance of the HBV surface antigen (HBsAg) in a small but substantial proportion of patients and thus it could be considered a possible cure for the disease. Despite the great improvements, several new challenges emerge. HBV infection following completeness of neonatal vaccination has been recognized in a significant proportion of children. Although most of these patients experience a silent and transient infection with spontaneous recovery, some become chronic HBV carriers. The post-vaccination HBV carriers present with several different serological patterns. Serum HBsAg can be either positive or negative, with or without co-existing anti-HBs [4Hsu H.Y. Chang M.H. Liaw S.H. Ni Y.H. Chen H.L. Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan.Hepatology. 1999; 30: 1312-1317Crossref PubMed Scopus (227) Google Scholar, 5Jin O.C. Ning C.W. Shiuan K. Keow L.G. Identification of hepatitis B surface antigen variants with alterations outside the "a" determinant in immunized Singapore infants.J Infect Dis. 1999; 179: 259-263Crossref PubMed Scopus (73) Google Scholar]. As such, the diagnosis of HBsAg-negative, post-vaccination HBV infection can only be made by detection of positive serum HBV-DNA. The latter condition is named "occult" HBV infection [[6]Raimondo G. Allain J.P. Brunetto M.R. Buendia M.A. Chen D.S. Colombo M. et al.Statements from the Taormina expert meeting on occult hepatitis B virus infection.J Hepatol. 2008; 49: 652-657Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar]. Previously, detection of viremia in occult HBV infection was mostly conducted by performing in-house PCR. Conceivably, significant variations of sensitivity and specificity among different laboratories are expected. PCRs targeted to at least two different regions of the HBV genome are usually required to obtain convincing results. With the availability of approved standardized qualitative and quantitative HBV-DNA assays, occult HBV infection can now be more reliably diagnosed. The etiology of post-vaccination HBV infection is not completely understood. Incomplete blockade of mother-to-infant transmission in high-titer maternal viremia appears to be an important risk factor. In infants of HBsAg-positive mothers carrying a high infectious risk, the post-vaccination HBsAg carrier rate can be as high as 11% [[7]Hsu H.M. Chen D.S. Chuang C.H. Lu J.C. Jwo D.M. Lee C.C. 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: 2231-2235Crossref PubMed Scopus (157) Google Scholar]. In infants born to HBV e antigen (HBeAg)-positive mothers, the reported post-vaccination HBsAg carrier rate ranged from 7.4% to 17.3% depending on different types of vaccines, injection schedules, and ages of assessment. In contrast, the overall post-vaccination HBsAg carrier rate, regardless of maternal status, and completeness of vaccination, is around or below 1%. The post-vaccination HBV viremia rate has also been assessed by detection of serum HBV-DNA. The rate ranges from 0% to 3.4% depending on reports from different countries [8Tsebe K.V. Burnett R.J. Hlungwani N.P. Sibara M.M. Venter P.A. Mphahlele M.J. 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: 3919-3926Crossref PubMed Scopus (86) Google Scholar, 9He 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: 1373-1377Crossref PubMed Scopus (53) Google Scholar, 10Hsu H.Y. Chang M.H. Ni Y.H. Chen H.L. Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan.Gut. 2004; 53: 1499-1503Crossref PubMed Scopus (156) Google Scholar, 11Chakvetadze C. Roussin C. Roux J. Mallet V. Petinelli M.E. Pol S. Efficacy of hepatitis B sero-vaccination in newborns of African HBsAg positive mothers.Vaccine. 2011; 29: 2846-2849Crossref PubMed Scopus (25) Google Scholar]. In a limited number of studies, the rate of post-vaccination occult HBV infection has been assessed, ranging from 0% to 10.9% [11Chakvetadze C. Roussin C. Roux J. Mallet V. Petinelli M.E. Pol S. Efficacy of hepatitis B sero-vaccination in newborns of African HBsAg positive mothers.Vaccine. 2011; 29: 2846-2849Crossref PubMed Scopus (25) Google Scholar, 12Mu S.C. Lin Y.M. Jow G.M. Chen B.F. Occult hepatitis B virus infection in hepatitis B vaccinated children in Taiwan.J Hepatol. 2009; 50: 264-272Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 13Xu L. Wei Y. Chen T. Lu J. Zhu C.L. Ni Z. et al.Occult HBV infection in anti-HBs-positive young adults after neonatal HB vaccination.Vaccine. 2010; 28: 5986-5992Crossref PubMed Scopus (48) Google Scholar]. In a study focusing on infants with HBsAg-positive carrier mothers, post-vaccination occult HBV infection was detected in only 2% of patients [[11]Chakvetadze C. Roussin C. Roux J. Mallet V. Petinelli M.E. Pol S. Efficacy of hepatitis B sero-vaccination in newborns of African HBsAg positive mothers.Vaccine. 2011; 29: 2846-2849Crossref PubMed Scopus (25) Google Scholar]. In this issue of the Journal of Hepatology, Shahmoradi et al. reported a surprisingly high post-vaccination occult HBV infection rate (28%) in children with HBsAg-positive mothers [[14]Shahmoradi S. Yahyapour Y. Mahmoodi M. Alavian S.M. Fazeli Z. Jazayeri S.M. 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: 515-521Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. In this study, 75 children born to HBsAg-positive mothers, previously immunized by HBIG and given prophylactic vaccine, were assayed for HBV DNA followed by direct sequencing. HBV DNA was detected in 21/75 (28%) children. All were positive for anti-HBs, while only 5 (24%) were positive for anti-HBc. Most notably, only 7 out of 75 mothers (9.3%) were HBeAg-positive. This unusually high rate in Iranian children suggests that besides risky contacts with highly infectious mothers, other factors such as HBV genotype, racial differences, and nursing style may be involved. In Iran, genotype D is the predominant genotype, which is different from most of the other common genotypes in the world. Whether this factor contributes to post-vaccination infection requires careful investigation. Delayed injection of HBIG >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 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]Bes M. Vargas V. Piron M. Casamitjana N. Esteban J.I. Vilanova N. et al.T cell responses and viral variability in blood donation candidates with occult hepatitis B infection.J Hepatol. 2012; 56: 765-774Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. 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 [16Hsu C.W. Yeh C.T. Chang M.L. Liaw Y.F. Identification of a hepatitis B virus S gene mutant in Lamivudine-treated patients experiencing HBsAg seroclearance.Gastroenterology. 2007; 132: 543-550Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 17Hsu C.W. Yeh C.T. Emergence of hepatitis B virus S gene mutants in patients experiencing hepatitis B surface antigen seroconversion after peginterferon therapy.Hepatology. 2011; 54: 101-108Crossref PubMed Scopus (35) Google Scholar]. These vaccine-escape-like mutants with reduced HBs antigenicity have been proposed to be a possible infectious source for post-vaccination HBV infection [[18]Clements C.J. Coghlan B. Creati M. Locarnini S. Tedder R.S. Torresi J. Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?.Bull World Health Organ. 2010; 88: 66-73Crossref PubMed Scopus (40) Google Scholar]. At this time, however, only silent and transient infection by drug resistant HBV mutants has been experimentally demonstrated in vaccinated chimpanzees [[19]Kamili S. Sozzi V. Thompson G. Campbell K. Walker C.M. Locarnini S. et al.Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model.Hepatology. 2009; 49: 1483-1491Crossref PubMed Scopus (71) Google Scholar]. 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]Lai M.W. Huang S.F. Hsu C.W. Chang M.H. Liaw Y.F. Yeh C.T. Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy.Antivir Ther. 2009; 14: 249-261PubMed Google Scholar]. 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, long-term consequence, and therapeutic strategy for these mutants remain unknown and await further investigation. The author declares that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.