Hepatitis E virus (HEV) is a significant public health concern worldwide. Pregnant women are at high risk of severe HEV infection. Various adverse outcomes in pregnant women related to HEV infection have been well documented in low-income and middle-income countries with poor sanitation. However, previous studies have provided inconsistent conclusions regarding the effects of HEV infection on the health of pregnant women and their infants in developed countries and contemporary China. In China, previous studies on HEV in pregnant women mainly focused on anti-HEV IgM and/or anti-HEV IgG. In this study, 4244 pregnant women were retrospectively analyzed for HEV-related markers. The positive rates of HEV antigen, HEV RNA, anti-HEV IgM, and anti-HEV IgG were 0.28%, 0.54%, 0.35%, and 10.49%, respectively. Among the 467 pregnant women who tested positive for at least one HEV-related marker, 92.93% (434) were positive for anti-HEV IgG only and 0.21% (1) were positive for HEV antigen, anti-HEV IgM, and anti-HEV IgG. Although the prevalence of anti-HEV IgG significantly increased with age, the prevalence of anti-HEV IgM, HEV RNA, and HEV antigen did not differ among pregnant women of different ages. Thirty-three pregnant women were positive for at least one of anti-HEV IgM, HEV antigen, and HEV RNA, and these individuals were recently or currently infected with HEV. None of the 33 pregnant women exhibited obvious clinical symptoms. Of the 33 pregnant women, 39.39% (13) experienced adverse fetal outcomes, including preterm birth, fetal distress, and low birth weight, the incidence of which was significantly higher than in pregnant women who were not recently or currently infected with HEV. These findings suggest that maternal HEV infection may impact the health of fetuses; thus, these results may contribute to the development of appropriate public health interventions for this population.

Chronic hepatitis E virus (HEV) infection occurs mainly in immunosuppressed populations. We describe an investigation of chronic HEV infection of genotype 3a in an individual without evidence for immune deficiency who presented hepatitis with significant HEV viremia and viral shedding. We monitored HEV RNA in plasma and stools, and assessed anti-HEV specific immune responses. The patient was without apparent immunodeficiency based on quantified results of white blood cell, lymphocyte, neutrophilic granulocyte, CD3+ T cell, CD4+ T cell, and CD8+ T cell counts and CD4/CD8 ratio, as well as total serum IgG, IgM, and IgA, which were in the normal range. Despite HEV specific cellular response and strong humoral immunity being observed, viral shedding persisted up to 10⁹ IU/mL. After treatment with ribavirin combined with interferon, the indicators of liver function in the patient returned to normal, accompanied by complete suppression and clearance of HEV. These results indicate that HEV chronicity can also occur in individuals without evidence of immunodeficiency.

Paslahepevirus balayani (bHEV), also known as hepatitis E virus (HEV), encompasses eight genotypes, five of which infect humans. Rats are natural reservoirs of Rocahepevirus ratti genotype 1 (HEV-r-1; rat HEV; rHEV), which has recently been implicated in viral hepatitis. Despite the antigenic divergence between bHEV and rHEV, studies on shared protective antibodies remain rare. Polyclonal and monoclonal antibody responses against bHEV and rHEV were analyzed using antibody enzyme-linked immunosorbent assays. The efficacy of six potent bHEV-elicited cross-reactive antibodies in preventing rHEV infection was evaluated via challenge assays in rats. Cryo-EM was performed to assess the structural basis for the differential protective efficacy of the six antibodies. The viral lysis ability of these antibodies was assessed by separately reacting purified HEV-b-1 and HEV-r-1 virions with each antibody. We determined that antibody responses to bHEV infection and vaccination possess limited cross-reactivity to rHEV and identified two cross-reactive antigenic sites within the E2s domain. Structural analysis and animal challenge studies pinpointed potent cross-reactive antibodies targeting antigenic site 1, indicating its prophylactic efficacy against rHEV. Conversely, antibodies recognizing antigenic site 2 were found to facilitate viral lysis of bHEV but not rHEV. These findings underscore the importance of antigenic site 1 in the design of broad-spectrum vaccines and therapeutics to mitigate the impact of diverse HEV genotypes on human health. IMPACT AND IMPLICATIONS: rHEV spillover to humans represents an unprecedented threat. Significant antigenic differences between rHEV and bHEV may exacerbate the impact of viral hepatitis. Our study reveals that cross-reactive human antibodies can offer protection against rHEV infection. Cross-protective antibodies targeting antigenic site 1 can be used to inform the development of practical strategies for preventing rHEV infection.

Hepatitis E virus (HEV) is an important public health burden worldwide, causing approximately 20 million infections and 70,000 deaths annually. The viral capsid protein is encoded by open reading frame 2 (ORF2) of the HEV genome. Most ORF2 protein present in body fluids is the glycosylated secreted form of the protein (ORF2^S). A recent study suggested that ORF2^S is not necessary for the HEV life cycle. A previously reported efficient HEV cell culture system can be used to understand the origin and life cycle of ORF2^S but is not sufficient for functional research. A more rapid and productive method for yielding ORF2^S could help to study its antigenicity and immunogenicity. In this study, the ORF2^S (tPA) expression construct was designed as a candidate tool. A set of representative anti-HEV monoclonal antibodies was further used to map the functional antigenic sites in the candidates. ORF2^S (tPA) was used to study antigenicity and immunogenicity. Indirect ELISA revealed that ORF2^S (tPA) was not antigenically identical to HEV 239 antigen (p239). The ORF2^S-specific antibodies were successfully induced in one-dose-vaccinated BALB/c mice. The ORF2^S-specific antibody response was detected in plasma from HEV-infected patients. Recombinant ORF2^S (tPA) can act as a decoy to against B cells. Altogether, our study presents a design strategy for ORF2^S expression and indicates that ORF2^S (tPA) can be used for functional and structural studies of the HEV life cycle.

Hepatitis E virus (HEV) is one of the most important public health issues around the world, and chronic HEV infection has been reported in immunosuppressed individuals. This study reported a male case, with very severe aplastic anemia (AA), who developed chronic hepatitis E after hematopoietic stem cell transplantation (HSCT). Abnormal alanine aminotransferase (ALT) appeared after HSCT and persisted for twenty-nine months. The case was seropositive for anti-HEV IgG and IgM after HSCT. Twenty-two months after HSCT, HEV RNA and antigen (Ag) testing were positive and persisted for five and seven months, respectively. Positive stains of HEV Ag were present in a liver biopsy sample. HEV Ag was present in bone marrow. The individual rapidly developed liver cirrhosis and was rescued by a regimen of oral ribavirin. These factors suggested there is a risk of HEV infection in HSCT recipients.