The 1942 Massive Contamination of Yellow Fever Vaccine: A Public Health Consequence of Scientific Arrogance.

In the late 1930s, the 17D vaccine against yellow fever was produced in record time. 17D was and is an excellent vaccine. Its rapid diffusion led, however, to several problems, the most important among them being the 1942 massive contamination of the vaccine distributed to the US Army by the hepatitis B virus. The US part of this story is relatively well-known, but its Brazilian part much less so. In 1940, scientists who were producing the 17D vaccine in Rio de Janeiro found that it was contaminated by an "icterus virus" that originated in normal human serum. They solved this problem through the exclusion of human serum from vaccine production, but failed to persuade their US colleagues to do the same. The Rio experts, aware of the potential pitfalls of a new technology, carefully supervised the consequences of their vaccination campaigns. They were thus able to rapidly spot problems and eliminate them. By contrast, US scientists, persuaded of their technical superiority and distrustful of warnings that originated from a "less developed" country, neglected to implement basic public health rules. A major disaster followed. (Am J Public Health. 2021;111(9): 1654-1660. https://doi.org/10.2105/AJPH.2021.306313).

Long-term evolution of hepatitis B virus genotype F: Strong association between viral diversification and the prehistoric settlement of Central and South America.

The genotype F (HBV-F) is an autochthonous Native American strain of the hepatitis B virus. In this study, we reconstruct the HBV-F long-term evolution under a hypothesis of co-divergence with humans in Central and South America, since their entry into the region 14.5-16 thousand years ago. The Bayesian phylogeographic reconstruction supported a virus-host co-expansion; however, two evolutionary scenarios would have been present. Whereas subgenotype F1 spreads along a Pacific coastal route and would have evolved associated with Central American and Andean cultures from the west of the continent, subgenotypes F2-F6 spread along the Atlantic coastline and inner pathways associated with communities inhabiting the tropical forest lowlands. Then, we propose a model for HBV-F evolution in which the selection of differential biological characteristics in these two main groups would be related to their evolution in host populations with different genetic backgrounds and dissimilar demographic conditions.

Origin and dissemination of hepatitis B virus genotype C in East Asia revealed by phylodynamic analysis and historical correlates.

Hepatitis B virus disease progression in East Asia is most frequently associated with genotype C (HBV/C). The increasing availability of HBV/C genetic sequences and detailed annotations provides an opportunity to investigate the epidemiological factors underlying its evolutionary history. In this study, the Bayesian phylogeography framework was used to investigate the origins and patterns in spatial dissemination of HBV/C by analyzing East Asian sequences obtained from 1992 to 2010. The most recent common ancestor of HBV/C was traced back to the early 1900s in China, where it eventually diverged into two major lineages during the 1930s-1960s that gave rise to distinct epidemic waves spreading exponentially to other East Asian countries and the USA. Demographic inference of viral effective population size over time indicated similar dynamics for both lineages, characterized by exponential growth since the early 1980s, followed by a significant bottleneck in 2003 and another increase after 2004. Although additional factors cannot be ruled out, we provide evidence to suggest this bottleneck was the result of limited human movement from/to China during the SARS outbreak in 2003. This is the first extensive evolutionary study of HBV/C in East Asia as well as the first to assess more realistic spatial ecological influences between co-circulating infectious diseases.

Molecular evolution and phylodynamics of hepatitis B virus infection circulating in Iran.

Previous local and national Iranian publications indicate that all Iranian hepatitis B virus (HBV) strains belong to HBV genotype D. The aim of this study was to analyze the evolutionary history of HBV infection in Iran for the first time, based on an intensive phylodynamic study. The evolutionary parameters, time to most recent common ancestor (tMRCA), and the population dynamics of infections were investigated using the Bayesian Monte Carlo Markov chain (BMCMC). The effective sample size (ESS) and sampling convergence were then monitored. After sampling from the posterior distribution of the nucleotide substitution rate and other evolutionary parameters, the point estimations (median) of these parameters were obtained. All Iranian HBV isolates were of genotype D, sub-type ayw2. The origin of HBV is regarded as having evolved first on the eastern border, before moving westward, where Isfahan province then hosted the virus. Afterwards, the virus moved to the south and west of the country. The tMRCA of HBV in Iran was estimated to be around 1894, with a 95% credible interval between the years 1701 and 1957. The effective number of infections increased exponentially from around 1925 to 1960. Conversely, from around 1992 onwards, the effective number of HBV infections has decreased at a very high rate. Phylodynamic inference clearly demonstrates a unique homogenous pattern of HBV genotype D compatible with a steady configuration of the decreased effective number of infections in the population in recent years, possibly due to the implementation of blood donation screening and vaccination programs. Adequate molecular epidemiology databases for HBV are crucial for infection prevention and treatment programs.

Phenotypic and Genotypic Shifts in Hepatitis B Virus in Treatment-Naive Patients, Taiwan, 2008-2012.

We examined the characteristic changes of hepatitis B virus (HBV) in antiviral drug treatment-naive patients referred for pretreatment evaluation in Taiwan during 2008-2012. Over time, we observed substantial decreases in the prevalence of HBV e antigen (HBeAg) and increasing prevalence of the precore G1899A mutation and HBV-DNA levels in HBeAg-positive patients.

Medical virology of hepatitis B: how it began and where we are now.

Infection with hepatitis B virus (HBV) may lead to acute or chronic hepatitis. HBV infections were previously much more frequent but there are still 240 million chronic HBV carriers today and ca. 620,000 die per year from the late sequelae liver cirrhosis or hepatocellular carcinoma. Hepatitis B was recognized as a disease in ancient times, but its etiologic agent was only recently identified. The first clue in unraveling this mystery was the discovery of an enigmatic serum protein named Australia antigen 50 years ago by Baruch Blumberg. Some years later this was recognized to be the HBV surface antigen (HBsAg). Detection of HBsAg allowed for the first time screening of inapparently infected blood donors for a dangerous pathogen. The need to diagnose clinically silent HBV infections was a strong driving force in the development of modern virus diagnostics. HBsAg was the first infection marker to be assayed with a highly sensitive radio immune assay. HBV itself was among the first viruses to be detected by assay of its DNA genome and IgM antibodies against the HBV core antigen were the first to be selectively detected by the anti-µ capture assay. The cloning and sequencing of the HBV genome in 1978 paved the way to understand the viral life cycle, and allowed development of efficient vaccines and drugs. Today's hepatitis B vaccine was the first vaccine produced by gene technology. Among the problems that still remain today are the inability to achieve a complete cure of chronic HBV infections, the recognition of occult HBV infections, their potential reactivation and the incomplete protection against escape mutants and heterologous HBV genotypes by HBV vaccines.

Mortality and morbidity among military personnel and civilians during the 1930s and World War II from transmission of hepatitis during yellow fever vaccination: systematic review.

During World War II, nearly all US and Allied troops received yellow fever vaccine. Until May 1942, it was both grown and suspended in human serum. In April 1942, major epidemics of hepatitis occurred in US and Allied troops who had received yellow fever vaccine. A rapid and thorough investigation by the US surgeon general followed, and a directive was issued discontinuing the use of human serum in vaccine production. The large number of cases of hepatitis caused by the administration of this vaccine could have been avoided. Had authorities undertaken a thorough review of the literature, they would have discovered published reports, as early as 1885, of postvaccination epidemics of hepatitis in both men and horses. It would take 4 additional decades of experiments and epidemiological research before viruses of hepatitis A, B, C, D, and E were identified, their modes of transmission understood, and their genomes sequenced.

The twenty-year story of a plant-based vaccine against hepatitis B: stagnation or promising prospects?

Hepatitis B persists as a common human disease despite effective vaccines having been employed for almost 30 years. Plants were considered as alternative sources of vaccines, to be mainly orally administered. Despite 20-year attempts, no real anti-HBV plant-based vaccine has been developed. Immunization trials, based on ingestion of raw plant tissue and conjugated with injection or exclusively oral administration of lyophilized tissue, were either impractical or insufficient due to oral tolerance acquisition. Plant-produced purified HBV antigens were highly immunogenic when injected, but their yields were initially insufficient for practical purposes. However, knowledge and technology have progressed, hence new plant-derived anti-HBV vaccines can be proposed today. All HBV antigens can be efficiently produced in stable or transient expression systems. Processing of injection vaccines has been developed and needs only to be successfully completed. Purified antigens can be used for injection in an equivalent manner to the present commercial vaccines. Although oral vaccines require improvement, plant tissue, lyophilized or extracted and converted into tablets, etc., may serve as a boosting vaccine. Preliminary data indicate also that both vaccines can be combined in an effective parenteral-oral immunization procedure. A partial substitution of injection vaccines with oral formulations still offers good prospects for economically viable and efficacious anti-HBV plant-based vaccines.

Milestones and perspectives in viral hepatitis B.

There have been numerous research milestones since the discovery of the hepatitis B virus (HBV) in the 1960s. These mark major advances in the serology and epidemiology of HBV infection, in identifying the wide clinical spectrum of acute and chronic hepatic diseases as well as the extrahepatic conditions induced by this virus, the molecular biology of the virus including its variants and mutants, its molecular diagnosis and monitoring, the host immune responses to the infecting virus, the pathogenesis and immunopathogenesis of liver disease as well as its natural course and outcome. These landmark discoveries are the firm background for current and future developments in treatment. There are three consecutive and partly overlapping chronological periods to treatment milestones beginning with recombinant standard interferon-alpha (IFN-α) in the 1980s, then oral antivirals from 1998 to the present and in 2005 pegylated IFN-α (PEG-IFN). The renewed interest in PEG-IFN-α treatment is now focused on both HBeAg-positive and HBeAg-negative chronic hepatitis B and it now also aims at HBsAg loss when associated with on-treatment monitoring of serum HBV DNA and HBsAg levels, resulting in the closest thing to a cure of hepatitis B. The impressive progress made in all aspects of hepatitis B research suggests that curative therapy may be developed for all patients and for all phases of HBV infection in the foreseeable future. However for the moment, realistic efforts should be made to make treatment as widely available and affordable as possible and to apply current therapies to significantly reduce HBV morbidity and mortality.

Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century.

In the past, transfusion-transmitted virus (TTV) infections were not uncommon. In recent years with advanced technologies and improved donor screening, the risk of viral transfusion transmission has been markedly reduced. Hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have all shown marked reduction in transmission rates. However, the newer technologies, including nucleic acid technology (NAT) testing, have affected the residual rates differently for these virally transmitted diseases. Zero risk, which has been the goal, has yet to be achieved. False negatives still persist, and transmissions of these viruses still occur, although rarely. It is known that HBV serological testing misses some infected units; likewise, HBV NAT-negative units have also been known to transmit the virus. Similarly, HIV minipool NAT-negative units have transmitted HIV, as recently as 2007; likely, these transmissions would have been prevented with single-unit NAT testing. Newer technologies, such as pathogen inactivation (PI), will (ideally) eliminate these falsely test negative components, regardless of the original testing method used for detecting the viruses.

Ten millennia of hepatitis B virus evolution.

Hepatitis B virus (HBV) has been infecting humans for millennia and remains a global health problem, but its past diversity and dispersal routes are largely unknown. We generated HBV genomic data from 137 Eurasians and Native Americans dated between ~10,500 and ~400 years ago. We date the most recent common ancestor of all HBV lineages to between ~20,000 and 12,000 years ago, with the virus present in European and South American hunter-gatherers during the early Holocene. After the European Neolithic transition, Mesolithic HBV strains were replaced by a lineage likely disseminated by early farmers that prevailed throughout western Eurasia for ~4000 years, declining around the end of the 2nd millennium BCE. The only remnant of this prehistoric HBV diversity is the rare genotype G, which appears to have reemerged during the HIV pandemic.

Clinical, epidemiological aspects, and trends of Hepatitis B in Brazil from 2007 to 2018.

Hepatitis B virus (HBV) infection is a concern for public health due to its high prevalence, high infectivity, morbidity, and mortality worldwide. Brazil presents a low HBV prevalence, but has considerable heterogeneity among its geographic regions. Here, we describe the epidemiological profile of HBV infection in different regions of Brazil during 2007-2018, as well as the historical trends associated with the infection. We conducted an observational, ecological time-series study using secondary data collected from the National Notifiable Diseases Information System (SINAN). Our findings suggest that HBV infection was more likely to occur in young, sexually active adults. Individuals from Northeast and Midwest regions were more likely to present acute HBV infection, while individuals from South region were more likely to present chronic HBV infection, reinforcing that specific strategies are required for each particular region. Additionally, we observed a general decreasing trend of infection starting in 2014, however there was an increasing trend of infection in men and in individuals over 40 years old. Although we observed a decreasing trend in HBV infection, active surveillance is needed to prevent HBV spread and possible epidemics, as well as encouraging the vaccination of adults, especially young adult males. Our findings can inform the conduct of large-scale observational studies to evaluate clinical, economical, and social impacts of HBV infections, leading to improved social policies. Finally, our results highlight the need to improve data quality and completeness of epidemiological data, minimizing eventual errors that can make prevention and control strategies difficult.

Public health policy for management of hepatitis B virus infection: historical review of recommendations for immunization.

Chronic hepatitis B virus (HBV) infection is the leading cause of cirrhosis, liver failure, and liver cancer, and an estimated 620,000 persons die annually from HBV-related liver disease (Goldstein et al., 2005; World Health Organization, 2000). Immunization with the HBV vaccine is the most effective means of preventing HBV infection and its consequent acute and chronic liver diseases such as cirrhosis and hepatocellular carcinoma. The HBV vaccine has been used against HBV in the United States since 1982 (Centers for Disease Control and Prevention, 1982); during the last 25 years, HBV vaccine policy continued to evolve in response to public health issues and epidemiologic data. Although the number of newly acquired HBV infections has substantially declined as a result of implementation of a national immunization program, the prevalence of chronic HBV infection remains high. The purpose of this article is to review the epidemiology of HBV, provide a historical review of health policies for HBV immunization, and summarize the recent evidence-based public health guidelines for management of HBV infection in the United States.

Origin and Health Status of First-Generation Africans from Early Colonial Mexico.

The forced relocation of several thousand Africans during Mexico's historic period has so far been documented mostly through archival sources, which provide only sparse detail on their origins and lived experience. Here, we employ a bioarchaeological approach to explore the life history of three 16th century Africans from a mass burial at the San José de los Naturales Royal Hospital in Mexico City. Our approach draws together ancient genomic data, osteological analysis, strontium isotope data from tooth enamel, δ13C and δ15N isotope data from dentine, and ethnohistorical information to reveal unprecedented detail on their origins and health. Analyses of skeletal features, radiogenic isotopes, and genetic data from uniparental, genome-wide, and human leukocyte antigen (HLA) markers are consistent with a Sub-Saharan African origin for all three individuals. Complete genomes of Treponema pallidum sub. pertenue (causative agent of yaws) and hepatitis B virus (HBV) recovered from these individuals provide insight into their health as related to infectious disease. Phylogenetic analysis of both pathogens reveals their close relationship to strains circulating in current West African populations, lending support to their origins in this region. The further relationship between the treponemal genome retrieved and a treponemal genome previously typed in an individual from Colonial Mexico highlights the role of the transatlantic slave trade in the introduction and dissemination of pathogens into the New World. Putting together all lines of evidence, we were able to create a biological portrait of three individuals whose life stories have long been silenced by disreputable historical events.

Excavating new facts from ancient Hepatitis B virus sequences.

Recently, two independent studies discovered 15 ancient Hepatitis B virus (aHBV) sequences, of which 7 dated back to the Neolithic age (NA) and the Bronze Age (BA). In the present research, all the available aHBV sequences were collectively re-analysed with reference to extant HBV diversity to understand the role of these aHBV genotypes in evolution of extant HBV genetic diversity. Several intergenotype recombination events were documented, which corroborated well with population admixture and ancient human migration. Present analyses suggested replacement of HBV genotype associated with early Neolithic European farming cultures by the migrating steppe people, during Bronze Age Steppe migration. Additionally, detailed analyses of recombinations revealed evolution of a number of extant genotypes and suggested their possible site of origin. Through this manuscript, novel and important findings of the analyses are communicated.

Advances in viral hepatitis: 50 years of Australian gastroenterology.

Viral hepatitis classification, treatments and pathogenesis has been increasingly defined over the past 50 years. Australian researchers have made significant contributions in the areas of viral hepatitis A vaccine development, treatment outcomes for chronic hepatitis B and C, the role of liver transplantation and the pathogenesis of injury and disease progression. This review outlines some of these contributions.