Discovery of Hepatitis E and Its Impact on Global Health: A Journey of 44 Years about an Incredible Human-Interest Story

Abstract

The story of the discovery of hepatitis E originated in the late 1970s with my extreme belief that there was a hidden saga in the relationship between jaundice and pregnancy in developing countries and the opportunity for a massive epidemic of viral hepatitis, which hit the Gulmarg Kashmir region in November 1978. Based on data collected from a door-to-door survey, the existence of a new disease, epidemic non-A, non-B hepatitis, caused by a hitherto unknown hepatitis virus, was announced. This news was received by the world community with hype and skepticism. In the early 1980s, the world watched in awe as an extreme example of human self-experimentation led to the identification of VLP. In 1990, a cDNA clone from the virus responsible for epidemic non-A, non-B hepatitis was isolated. Over the years, we traversed three eras of ambiguity, hope, and hype of hepatitis E research and conducted several seminal studies to understand the biology of HEV and manifestations of hepatitis E. Many milestones have been reached on the long and winding road of hepatitis E research to understand the structure, biology, and diversity of the agent, changing the behavior of the pathogen in developed countries, and the discovery of a highly effective vaccine.

Keywords: acute liver failure; acute-on-chronic liver failure; discovery; epidemic; hepatitis E; hepatitis E virus; non-A, non-B hepatitis; pregnancy; sporadic; transmission.

Figure 1

Incidence and severity of epidemic hepatitis E in pregnancy. Data were collected through a door-to-door survey of 15 villages during the Gulmarg Kashmir epidemic of 1978–1979. Pregnant women acquired HEV infections more often than men and non-pregnant women (15–45 years), in all three trimesters of pregnancy. Acute liver failure and consequent case fatality rates in HEV-infected pregnant women were higher than in HEV-infected men and non-pregnant women (15–45 years), selectively in the third trimester of pregnancy. HEV-infected pregnant women had high obstetric complications and had no evidence of malnutrition. The epidemic was caused by HEV-gt1.

Figure 2

Seminal studies conducted in Kashmir on hepatitis E in three eras as defined. Each block identifies one published study protocol with the aim of the study (in bold) and consequent results. The year each study was published is shown. The right lower quadrant has 6 photographs taken of the region during the epidemic (1978–1979), showing the author standing in hard weather conditions (top picture), author along with the team conducting a door-to-door survey (second top), latrine sewage draining into waterways, (third left) and water collected from downstream (third right). The lower left image depicts Ningli Nallah flowing through the mountainous range and the lower right image depicts its multipurpose usage (sewage disposal, collection of drinking water, etc.). References include [31,32,33,34,35,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75].

Figure 3

Proposed pathogenesis of adverse relationship between hepatitis E and pregnancy. See text for details. AIAVH = anicteric acute viral hepatitis, HEV-ALF = hepatitis E virus-related acute liver failure. IAVH=Icteric acute viral hepatitis.

Figure 4

The long and winding road of milestones over the years in hepatitis E research. Each study was a turning point in understanding hepatitis E. Left lower quadrant depicts native HEV with T = 3 capsid morphology. References include [31,32,33,35,42,53,66,71,78,101,102,103,104,105]. Due to space constraints, only selected milestones are shown.

Figure 5

Hepatitis E virus: classification, nomenclature, and diversity. Members of the Hepeviridae family are assigned to two subfamilies, five genotypes, and ten species, and infect over a dozen species of hosts in the animal kingdom. Human infections occur in several ways and are depicted by red arrows.

Figure 6

Structure of hepatitis E virus and genomic organization. For details, see the text in Hepatitis E Virus section.

Figure 7

Proposed replication of hepatitis E virus. For details, see the text about hepatitis E replication.

Figure 8

Evolutionary history of hepatitis E virus. The times to the most recent common ancestors (tMRCAs) were calculated using BEAST to conduct a Bayesian analysis of HEV. For details, see text on HEV evolution.

Figure 9

Global distribution of hepatitis E virus.

Figure 10

Hepatitis E ORF2 expression, self-assembly, and virus-like particles with native HEV (T = 3) and assembled VLP (T = 1). HEV ORF2 proteins with different lengths have been expressed and purified in several systems in order to determine their particle-forming properties [154]. The native HEV particles have 660 aa with T = 3 icosahedral symmetry and 180 units of the ORF2 protein, encircling HEV RNA [102]. In the baculovirus insect cell system, the HEV capsid protein can self-assemble into either a large or a small VLP [156]. In the E. coli system, the shortest proteins, termed E2 and E2a, form hexamer protrusions and E2s form dimers [157,158]. Adding 26 amino acids toward the N-terminus of the pE2 peptide results in higher-order assembly structure p239 (368–606 aa), which is highly immunogenic [159]. Due to space constraints only two expression systems are depicted and selective assembled VLP are shown.