Introduction

Hepatitis E infection, caused by the hepatitis E virus (HEV), is the fifth known type of human viral hepatitis and it is considered to be the most common cause of jaundice, acute liver failure, and acute viral hepatitis1, 2, 3, 4, 5, 6. Despite being an important viral pathogen, HEV and its origin remain involves many unanswered questions7, 8. The mechanisms of HEV pathogenesis and its replication are poorly understudied, mostly due to the lack of reliable diagnostic methods7, 8. HEV is common in developing countries, causing small- and large-scale outbreaks. In developed countries, human infections occur mainly through zoonotic transmission1.

Although most HEV infections cause mild hepatitis, infection is usually more severe in pregnant women1. Furthermore, HEV infection during pregnancy often leads to premature births, a low birth weight, and infant death9, 10, 11. In addition, chronic HEV infection has been reported in immunocompromised patients, transplant recipients, and patients receiving chemotherapy12, 13, 14. According to the World Health Organization (WHO), there are an estimated 20 million HEV infections every year globally. Of these cases, approximately 3.3 million develop into symptomatic cases. In 2015, HEV caused an estimated 44,000 deaths worldwide, accounting for 3.3% of the mortality due to viral hepatitis15.

Vaccines have had an enormous impact on public health around the world, saving millions of lives. Vaccination has the potential to reduce healthcare costs, lower death rates, and extend life expectancy16, 17. The critical property of vaccines is to stimulate the immune system against diseases. Some vaccines also protect against infection. Since the 1990s, the immunization/vaccination coverage has increased substantially. As a result, millions of lives have been saved. According to the WHO statistics, vaccines save more than 2.5 million deaths per year18, 19. At present, vaccines are available for more than 30 life-threatening viral and bacterial diseases20, 21. Vaccinations prevent illnesses and death associated with infectious diseases such as diphtheria, influenza, measles, pneumonia, polio, and pertussis/whooping cough22. Several HEV vaccine candidates have progressed into the clinical development stage, and one of them has been approved and licensed only in China23.

This review aims to summarize the current development of HEV vaccines and the key challenges that are a part of vaccine development and deployment.

Transmission

In countries with limited resources, HEV is most frequently transmitted through drinking water contaminated with fecal matter. In Southeast Asia, the number of HEV cases increases during the rainy season24. Nevertheless, case numbers have been increasing in the dry season when the drinking water supplies are not flooded or contaminated25. Furthermore, the low levels of household sanitation may also increase the risk of HEV infection26.

In addition, HEV transmission has been reported via blood and nosocomial routes27, 28. It is also well documented that a pregnant woman can transmit HEV to her unborn fetus25, 26, 27, 28, 29. No HEV transmission through sexual intercourse has been documented25, 26, 27, 28, 29.

HEV taxonomy and geographical distribution

HEV is a small (27–34 nm) single-stranded positive-sense RNA virus from the family and genus (Figure 1A)31, 32. The virus has a genome of about 7.2 kb in length with three open reading frames (ORF1, ORF2, and ORF3) (Figure 1B)4, 31, 32, 33.

HEV causes infections worldwide but it is more common in low- and middle-income countries with limited access to clean drinking water, acceptable hygiene practices, proper sanitation, and health services. Both sporadic cases and outbreaks have been documented15, 34, 35. HEV cases are commonly observed to have two different patterns: (i) resource-limited regions with frequent water contamination and (ii) regions with safe drinking water supplies. The HEV infections in developed regions are generally triggered by zoonotic transmission, mainly through undercooked pork products15, 36, 37, 38.

A recent study reported that the seroprevalence of HEV among countries in Southeast Asia ranged from 2% (Malaysia) to 77.7% (Lao People's Democratic Republic)39.

Another recent meta-analysis including 1,099,717 subjects from various countries worldwide reported that the HEV IgG and IgM antibody seropositivity was 12.47% (95% CI: 10.42–14.67) and 1.47% (95% CI: 1.14–1.85), respectively30. The highest HEV IgG seropositivity was reported in Africa, followed by Asia, Europe, North America, South America, and Oceania, as presented in Figure 2. In total, the HEV RNA seropositivity in the general population was 0.20% (95% CI: 0.15–0.25)30. The potential key risk factors for HEV IgG antibody positivity were living in rural areas, exposure to soil, the consumption of raw meat, traveling to high disease burden regions, blood transfusion, contact with dogs, and a low level of education30.

HEV vaccine development

After the discovery of HEV in 1981, attempts have been made to develop effective HEV vaccines40, 41. Currently, the advancement of an attenuated or inactivated vaccine is not feasible because HEV cannot be grown reproducibly in cell culture systems. Instead, the development of recombinant protein or nucleic acid-based vaccines has seen significant progress42, 43.

Meanwhile, human papillomavirus and HEV virus-like particle (VLP) vaccines consist of nanoparticles of 30 and 60 nm in diameter that contain only the viral capsid protein and no lipids. For HEV VLPs, the central building block is the pORF2 E2 dimer44, 45.

At least 11 experimental HEV vaccines have been assessed in non-human primates with a viral challenge46. Numerous vaccines have been discovered using a cell culture system for HEV47, 48. The results obtained from a study on avian HEV in chickens suggested that oral vaccination using expressing a part of the avian HEV-ORF2 protein can counteract hepatitis and liver injury caused by a HEV infection49. On the other hand, an alternative cell culture system, the A549 cell line that does not require RNA transfection, was found to support the partial replication of genotype-1 HEV from a patient blood serum sample50. The preclinical studies on HEV vaccines are presented in Table 1. The registered clinical trials on HEV vaccines are presented in Table 2.

HEV vaccine efficacy

Several studies have been conducted to develop HEV vaccines and assess their efficacy, of which only three studies have registered for clinical trials as shown in Table 3. In China, a phase III clinical trial was conducted among participants (n = 112,604) aged 16 – 65 years old. After receiving the complete 3 doses, the Hecolin® HEV p239 vaccine showed 100% (95% CI, 72–100) efficacy. Additionally, the efficacy was 96% (95% CI, 66–99) among the individuals who received at least one dose73. The HEV p239 vaccine is immunogenic and well-tolerated. It induces immunity against HEV infection in the age group older than 65 years74. Another study conducted in Bangladesh among pregnant women showed that the HEV p239 vaccination induces immunogenicity against HEV infection and prevented maternal and neonatal deaths due to HEV infection75.

In Nepal, another clinical trial (898 in the vaccine group and 896 in the placebo group that received three vaccine doses) of a recombinant HEV protein (rHEV) vaccine showed 95.5% (95% CI, 85.6–98.6) efficacy72. The intention-to-treat analysis also strengthens the promise of this vaccine. After administering the first dose of the rHEV vaccine, the estimated efficacy was 88.5 to 89.9%72.

The HEV vaccine p179 showed good safety and tolerance after a phase I clinical trial conducted among participants (n = 120, 16 – 65 years) in China. Three different dosages, 20, 30, and 40 μg of HEV p179 vaccines, were received by the experimental groups with 30 μg HEV vaccine p239 Hecolin® used as a control. Vaccination occurred at 0-, 1-, and 6-month intervals. The incidence of solicited local adverse reactions (ARs) in the experimental groups was significantly lower than in the control group (P = 0.027). However, no significant difference was reported between the incidence of solicited total and systemic ARs in the experimental and control groups. Thus, the tested dosages of the HEV p179 vaccine are well tolerated and safe with no serious adverse reactions76.

The use of two truncated ORF2 proteins (54KDa and 26KDa) as a vaccine showed that they have immunogenicity. It acts as a nanoparticle against HEV infection77. A study carried out in China reported that antibody loss is significantly lower for innate immunity compared to immunity acquired from vaccination after 10 years78. The recombinant VLP-based Hecolin® HEV vaccine available in China acts as a trivalent vaccine. This vaccine produces an immune response against HEV infection, blocks the activity of novavirus binding to histo-blood group antigens, and inhibits astrovirus infection79, 80. The Hecolin® vaccine completed its phase III clinical trial. It has been licensed in China but is not yet available commercially. Furthermore, to launch the HEV vaccine globally, the safety and efficacy data of HEV p239 is needed for high-risk and immunocompromised groups, including pregnant women and individuals with chronic liver disease, HIV, and immune disorders81, 82, 83, 84.

Key challenges in vaccine distribution

Developing a vaccine is a tremendous challenge, but a considerable challenge will still exist even when one becomes available, specifically getting enough people vaccinated. Misinformation and fear are two of the leading causes of low vaccination coverage. Some of the challenges in the distribution of vaccines are shown in Figure 3. A crucial factor when distributing vaccines is the resource constraints faced by the state or local health departments. Funding issues become severe in developing and undeveloped countries85. Providing a complete number of doses according to the need is itself a challenge. Other logistical issues include monitoring, tracking vaccine safety, identifying a broad network of sites for administration, and ensuring that the cold chain requirements are met85.

Differing rules and regulations across the jurisdictions can also influence the success of vaccine distribution and availability. Covering the vaccine's expenses with insurance enhances the availability of vaccines to individuals. Despite this, limitations remain and some individuals face difficulties accessing the vaccine. Addressing racial and ethnic differences is an unprecedented challenge and has a significant impact on communities. Ensuring the equal and easy availability of a vaccine regardless of any ethnic disparities could improve the success of the vaccine overall. Finally, achieving a high rate of vaccination directly depends on the people’s trust in and willingness to receive the vaccine. To some extent, all vaccines must face the public's confidence and this issue must be overcome through robust communication and trust-building efforts.

Adverse reactions to vaccines

Some common local and systematic reactions such as swelling, pain, irritability, drowsiness, rashes, or fever have been detected after vaccination85. Most commonly, erythema at the injection site is reported, but using a longer needle (25 mm 16 mm) may decrease the prevalence of injection-site reactions85, 86. Some collaborations have been established to monitor the adverse reactions of vaccines. Vaccine Safety Datalink, a col­laboration between the Centers for Disease Control and Prevention and nine health care orga­nizations, was established in 1990 to investigate rare and serious adverse effects of vaccines. The Vaccine Adverse Event Reporting System also monitors vaccine safety for newly approved or recommended vaccines87, 88. When considering recommended childhood vaccines, many parents are more concerned about the theoretical risks and real effects89.

Some vaccines, such as the measles vaccine, are associated with allergic reactions90. The varicella vaccine and MMR vaccine are associated with rashes, which appear between 9 to 16 days after vaccination91.

Conclusions

There is a pressing need for a globally available HEV vaccine. Routine vaccination should be implemented in countries with endemic HEV with a special emphasis on pregnant women and immunocompromised individuals. Improving access to clean drinking water and the sanitary disposal of human waste are the two most critical strategies to prevent HEV infections. Further understanding of the exact HEV burden in endemic areas would assist in developing a vaccination policy if a commercially HEV licensed vaccine becomes available worldwide. However, in most underdeveloped countries where HEV is a leading cause of acute viral hepatitis, there is a lack of epidemiological data. The endemic countries need to begin monitoring viral hepatitis and stress etiological rather than syndrome diagnosis to benefit from the vaccine optimally.

HIGHLIGHTS

ABBREVIATIONS

CDC: Centers for Disease Control and Prevention

FDA: Food and Drug Administration

HEV: Hepatitis E virus

HBGAs: Histo-blood group antigens

HPV: Human papillomavirus

ORF: Open reading frame

rHEV: HEV recombinant protein

VAERS: Vaccine Adverse Event Reporting System

VLPs: Virus-like particles

US: United States

WHO: World Health Organization

ACKNOWLEDGMENTS

The authors acknowledge their respective universities.

AUTHOR’S CONTRIBUTIONS

Tauseef Ahmad: Conceptualization, data collection and writing-original draft preparation. All the authors potentially contributed, and approved the final version for publication.

FUNDING

This review received no financial support from any government or private sector.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

CONSENT FOR PUBLICATION

Not applicable.

COMPETING INTERESTS

The authors declare that they have no competing interests.