Is Hepatitis A Under Control? The Viral Sequencing Revolution
"How viral sequencing can revolutionize hepatitis A vaccination strategies and emergency response."
Hepatitis A virus (HAV) affects approximately 10 million people each year, remaining a significant global health concern despite the availability of an effective vaccine since 1995. Interest in HAV has waned over the last few decades, overshadowed by hepatitis B and C, yet its impact remains substantial.
HAV infection often goes unnoticed, particularly in children in high-incidence countries. This underestimation, coupled with limited research in developed countries with low incidence rates, necessitates further investigation into virus evolution and improved preventative measures, especially during outbreaks.
The multi-country HAV outbreaks in Europe between 2016 and 2017, predominantly affecting men who have sex with men (MSM), highlight the urgent need for enhanced control strategies in emergency situations. Viral sequencing is key to determining the virus mutations and strains that have spread.
Recent U.S. Trends
CDC’s HepTracker lets users view hepatitis A case-surveillance and viral-hepatitis mortality data to monitor trends and inform public-health programs. After annual increases from 2015 through 2019, reported hepatitis A cases began decreasing in 2020; the rate of newly reported cases fell 28% from 2022 to 2023. Since 2016, outbreaks in multiple U.S. states have been driven primarily by person-to-person spread among adults who use drugs and experience homelessness. CDC describes surveillance as a way to track disease trends, evaluate prevention and control activities, and help direct funding.
Sequencing Methods and Challenges
HAV outbreak investigations have often used partial VP1–2A genomic sequences, while whole-genome sequencing can provide more detailed resolution for genotyping and phylogenetic analysis. A custom HAV assay was reported to streamline genotyping and produce phylogenetic trees with greater resolution than VP1–2A sequencing alone. However, direct whole-genome sequencing remains challenging because HAV samples can have low viral titers and the virus lacks a cell-culture system. One reported strategy adapts a commonly available SARS-CoV-2 sequencing kit, and a similar IMAP Illumina kit, to help viral-surveillance laboratories obtain HAV sequences.
From Epidemic Jaundice to Viral Hepatitis
Illnesses resembling hepatitis A have been described since antiquity, and the contagious nature of jaundice was suspected as early as the eighth century AD. Viral hepatitis was still often described as “epidemic jaundice” in historical accounts, including records from military campaigns between the eighteenth and twentieth centuries. The two forms of viral hepatitis were clearly differentiated during World War II. Later, the discovery of Australia antigen and its association with hepatitis B helped guide efforts to identify other hepatitis viruses.
Vaccine Shortages and the Importance of Tailored Vaccination Strategies
The World Health Organization (WHO) recommends universal HAV vaccination, including two doses in national immunization schedules for children >1 year, based on incidence data and cost-effectiveness. However, some low-income countries and outbreak responses implement a single-dose regimen. Recent data suggests that single-dose regimens may result in a growing number of susceptible adults, as seen in the USA, where outbreaks persist due to lower hepatitis A immunization rates compared to other vaccines.
- A limited sample size.
- The absence of information on neutralizing antibodies to HAV.
- The inclusion of immunosuppressed (HIV-infected) patients, a condition that may impact the course of HAV infection.
New Directions in HAV Research
A 2025 study on whole-genome sequencing of HAV examines adapting high-throughput sequencing to foodborne viruses. Another 2025 paper describes complete viral genomes as a way to gain insight into genetic variants. A review focused on Mexico notes that HAV infections, which are vaccine-preventable, are often underestimated. Separately, a report on a Krakow outbreak describes the highest increase between March and July 2017, with men who have sex with men predominating among those affected.
Limits of Sequencing Evidence
Whole-genome sequencing of HAV remains difficult in part because viral loads can be extremely low and next-generation sequencing has limitations. Partial VP1/2A sequences are commonly used for molecular epidemiology, but whole-genome analysis can offer broader sequence information. A 2020 study also identifies PCR amplification artefacts and ambiguities in de novo assembly as factors that limit HAV whole-genome sequencing. In discussing vaccine-escape variants, a commentary notes limitations in the underlying evidence, including a small number of samples, missing information on neutralizing antibodies, and inclusion of immunosuppressed participants whose effects on infection could not be ruled out.
Looking Ahead: Sequencing for Proactive Prevention
The global impact of HAV outbreaks is further evidenced by a 2016 outbreak in the Americas, particularly in Chile, primarily affecting MSM. Viral sequences from Chile were linked to the V16-25801 cluster, a predominant strain in Europe, suggesting potential intercontinental transmission.
Broader Capture for HAV Genomes
A 2023 proof-of-concept study introduced a hybrid-capture oligo panel for whole-genome sequencing of all six human-pathogenic HAV subgenotypes. The study reports that the panel had higher sensitivity than some conventional genotyping assays. This approach points toward sequencing methods designed to capture a broader range of HAV genomes, though the cited source describes it as a proof of concept.
A Widespread Infection Often Overlooked
A 2018 article reports that HAV affects approximately 10 million people annually and is the most common cause of acute viral hepatitis worldwide. It also observes that HAV research has been largely eclipsed in recent decades by greater interest in hepatitis B and hepatitis C. These points underscore the scale of HAV alongside the comparatively limited attention described by that source.
These findings underscore the need for countries in epidemiological transition to rapidly distinguish between endemic outbreaks and those related to sexual transmission among MSM, as different control measures may be necessary. The study of vaccine-escape variants is critical in both endemic and non-endemic settings, given their potential to expand into the general population.
Novel sequencing strategies can reveal biological events during infections that appear under control. Understanding the co-evolution of HAV and the human host, leading to the selection of antigenic variants, offers new avenues for investigation. Enhanced monitoring, detailed guidelines for cases, and global scrutiny of vaccine-escape variants are essential for constructing predictive models of infection evolution and defining effective vaccination strategies.