The remarkable success of the vaccine for a killer virus: Hepatitis B
Authors: Carla S. Coffin
Journal: Hepatology (2022)

SEE ARTICLE ON PAGE 1566 Abbreviation NHANES National Health and Nutrition Examination Surveys In 1976, Dr. Baruch S. Blumberg was awarded the 1976 Nobel Prize in Medicine for “his discoveries concerning new mechanisms for the origin and dissemination of infectious diseases,” that is, HBV.[1] Dr. Blumberg’s work, together with medical microbiologist Dr. Irving Millman, led to the development of the first HBV vaccine, saving millions of lives. In his inspiring personal account, The Hunt for a Killer Virus (2002),[1] Dr. Blumberg muses that whereas it may be tempting fate to be too optimistic, it appears likely that within the next few decades the virus will be effectively controlled or possibly eradicated. More than 1 billion doses of the HBV vaccine have been given worldwide, leading to a striking decrease in new infections in many countries previously endemic for HBV.[2] Unfortunately, in 2022, nearly four decades after approval of the first HBV vaccine, HBV is still one of the most deadly viruses affecting humans. The World Health Organization (WHO) estimates that 296 million persons are living with chronic hepatitis B (CHB) and almost a million deaths each year are attributable to complications of HBV infection, including HCC, with greatest burden in the WHO Africa and Asia‐Pacific region.[2,3] The recent study in Hepatology by He et al.[4] examined the effects of the HBV vaccine in a nonendemic country. The study used data sets from 10 National Health and Nutrition Examination Surveys (NHANES) conducted by the Centers for Disease Control and Prevention (CDC) from 1999 to 2018. The survey data sets included participants ≥6 years of age with self‐reported HBV vaccination history completed in the immunization questionnaire section and HBV serological testing. In participants >18 years of age, robust linkage to the NHANES Mortality File from 1999 to 2014 was used to determine the primary outcome of all‐cause mortality. In >60,000 participants included, >40% (~29,000) were fully vaccinated (Table 1). Vaccinated persons had a higher prevalence of vaccine‐induced immunity compared to unvaccinated (47.2% vs. 7.4%), with >85% vaccine effectiveness in those >20 years of age. Interestingly, HBV vaccination was also associated with reduced all‐cause and cancer‐related mortality, but not for cardiovascular‐related deaths. The researchers conclude that in the universal HBV vaccination era, the vaccine showed substantial effectiveness against HBV infection for at two decades and was associated with reduced risk of mortality. Key findings deserve highlighting from this study. The importance of universal birth‐dose vaccination in the fight against HBV even in non‐HBV‐endemic countries The vast majority of unvaccinated children who contract HBV at <1 year of age become chronically infected.[2] The USA is considered a low‐endemic region for HBV and has recommended universal infant vaccination since 1991. However, a recent study from the USA/Canada Hepatitis B Research Network of hepatitis B in children found that almost all (98%) had acquired HBV through vertical transmission, including 26% of pediatric cases who were born in the USA or Canada.[5] Indeed, in some Canadian judications, health policy advisors continue to argue that in a low‐HBV‐endemic region, prenatal screening programs and related interventions can effectively prevent vertical transmission without need for a universal infant vaccination program. This policy is refuted based on results from a recent descriptive study using administrative lab data in Ontario, Canada, which identified inadequate prenatal HBV screening and/or gaps in maternal HBV care and diagnosis of pediatric HBV infection in Canadian‐born children, even before they were actually eligible for the adolescent HBV vaccine program.[6] Their findings are reiterated by the current study, in that adolescent catch‐up vaccination had no significant effect against CHB infection, and delaying vaccination would miss many infections acquired during infancy and early childhood in the USA. The accumulated data underscore the need for North American and international health communities to ensure implementation of universal birth‐dose HBV vaccination programs. Long duration of protection against HBV following birth‐dose vaccination Although most studies have reported overall decreasing prevalence, there are limited data on individual‐level effectiveness in low‐endemic countries. The duration of protection is unknown or based on data from small studies. It is a subject of debate whether delaying the HBV vaccine until pre‐adolescence should be preferred and more cost‐effective in nonendemic countries, because of waning immunity and unknown extent of lifetime protection after primary vaccination at birth.[7] However, changing demography, increasing immigration, and current vaccine costs make the cost‐benefit ratios, even in low‐endemicity countries, strongly in favor of universal birth‐dose HBV vaccination. The NHANES does not collect the year of vaccination. Immunization data were collected by self‐reported (or proxy) responses, which are subjected to recall bias, but combined with HBV serological testing to categorize groups (i.e., antibody to HBV surface, core, and HBV surface antigen) for each age group (Fig. 2). The NHANES specimen biorepository[8] is not routinely tested for more‐sensitive molecular (i.e., HBV DNA) tests, which is recommended, by some expert recommendations, to confirm the diagnosis of past or resolved HBV infection attributable to declining antibody titers.[9] Nevertheless, the data contribute to mounting evidence on the duration of immunity without need for booster doses up to at least 20 years after primary immunization with currently approved vaccines in most children. A two‐dose HBV vaccine with a novel adjuvant was recently approved in the USA and found to be more effective in adults at risk for suboptimal response.[10] Additionally, a randomized controlled trial in Israel comparing standard‐of‐care HBV vaccine (i.e., Engerix‐B) to a three‐antigen HBV vaccine (Sci‐B‐Vac) showed greater efficacy in prevention of mother‐to‐child transmission and higher HBV surface antibody titers at 1 year.[11] Further studies with novel vaccine formulations are needed in the general pediatric subpopulation in regard to long‐term antibody response and immunity, but may be a future alternative for improved neonatal HBV vaccine programs. The mortality benefits of HBV vaccination HBV is the first widely used vaccine to prevent liver cancer, with striking decrease in incidence and mortality from HCC in children and adolescents in HBV‐endemic regions.[12] The study is one of the largest to highlight the benefits of receiving the HBV vaccine in all‐cause mortality in a non‐HBV‐endemic region. However, persons vaccinated were more likely to be younger, born in the USA, female, other ethnicity, lower poverty index, having health insurance, and overall better health condition. Furthermore, HBV vaccine‐induced immunity was associated with reduced mortality, albeit with only borderline significance, and remained protective even after adjusting for socioeconomic factors and health‐seeking behaviors in their model (Table 2; Figs. 4 and 5). The researchers acknowledge that the HBV vaccine may be generally protective against liver disease and other cancer development, but require longer duration of follow‐up, especially for liver‐related mortality. Moreover, their conclusions are intuitive, in that persons with structural barriers, socioeconomic inequalities, and inequitable access to health care and vaccination would be less healthy.[13] The COVID‐19 pandemic has exacerbated existing health care disparities, and challenges in the public health system may yet offer opportunities to integrate and leverage resources to also achieve HBV elimination (i.e., rapid point‐of‐care testing, vaccine implementation). In summary, the study uses a large, comprehensive, and nationally representative data set to show the benefits of HBV vaccination against HBV infection in a nonendemic country for at least 20 years. The HBV vaccine is the most important tool we have in the global fight against hepatitis B. The current study highlights the success of the HBV vaccine, especially in younger Americans. Continued global efforts with universal infant vaccination and expansion to adult populations will preserve the legacy of Dr. Blumberg and ensure that he did not tempt fate with his optimism for eradicating HBV as a public health threat worldwide. CONFLICT OF INTEREST Dr. Coffin has received investigator initiated research grants from Gilead and Janssen. She is a consultant for Altimmune with funds directed to the Canadian HBV Network, c/o University of Calgary.