Thirty years of hepatitis A epidemiology and vaccine studies: A narrative review of lessons learned in Alaska

Abstract

Hepatitis A virus (HAV) is an RNA virus transmitted by fecal-oral contamination. HAV is usually asymptomatic in young children who shed the virus, leading to infection in susceptible adults who develop symptomatic hepatitis. This article reviews the epidemiology of HAV infection in Alaska and results of hepatitis A vaccine (HepA) studies conducted in Alaska, including evidence that routine early childhood HepA vaccination can eliminate transmission in an area that previously experienced repeat outbreaks. Historically, Alaska had periodic large HAV outbreaks. Alaska was the site of both Phase 3 and 4 clinical trials of the HepA vaccine, one of which demonstrated that only one dose of HepA vaccine administered to susceptible persons in communities experiencing an active outbreak could stop transmission in 4–8 weeks. Evidence indicates that the HepA vaccine offers protection for at least 25 years for most individuals, however, data on the durability of immunity beyond this period is lacking, particularly among people vaccinated as young children. We discuss future considerations for continued control of hepatitis A in Alaska.

Introduction

Hepatitis A virus (HAV) is a highly infectious fecal-oral pathogen that can be transmitted through person-to-person contact and remain viable for several months in water and in food, surviving freezing temperatures. Though an uncommon cause of liver failure, HAV infections can lead to acute hepatitis, which can be severe and disrupt daily activities. Among adults and older children infected with HAV, approximately 70% will develop symptoms such as jaundice [1]. In contrast, young children infected with HAV are usually asymptomatic, often exhibiting a weaker and delayed viral immune response with prolonged viral shedding that can lead to infection in susceptible adults who are close contacts [2]. In rare cases, hepatitis A can cause liver failure and even death. This is more common in older people and in people with certain serious health issues, such as chronic liver disease [2].

To mitigate the risk of transmission, the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practice (ACIP) recommended the hepatitis A vaccine (HepA) for all children aged 12–23 months (since 2006), unvaccinated children aged 2–18 years (since 2020, with individuals aged ≥2 years in high-incidence areas since 1996), and unvaccinated adults at risk for HAV infection (since 1996 for those traveling to high-incidence areas, those who use drugs, and men who have sex with men; and since 2019 for those experinecing homelessness) [2,3]. While evidence suggests long-term immunity among individuals with prior HAV infections, the duration of immunity conferred by childhood vaccination remains uncertain, raising concerns about potential susceptibility to HAV infection in adulthood [2]. Unlike other childhood vaccines such as tetanus, pertussis, and diphtheria, which require booster doses in adulthood, it is hypothesized that the longer incubation period of HAV infections may allow more time for a potentially slower reactivation of immune memory after re-exposure as an adult, eliminating the need for booster doses decades after the primary childhood vaccination.

Historically, communities in Alaska have been disproportionately affected by hepatitis [4,5]. This is particularly true for some remote Alaska Native communities that lack in-home piped water and sewage systems [6,7]. Public health organizations in Alaska have performed several pre-licensure studies of immunogenicity and efficacy of recombinant vaccines as well as long-term protection studies involving individuals vaccinated as children [5,8–10]. To address a knowledge gap regarding persistence of vaccine immunity into adulthood, in this piece, we review HAV epidemiological studies performed in Alaska before and after HepA vaccine introduction, evaluate the evidence for the duration of protection after HepA vaccine administration, and discuss future considerations for continued control of hepatitis A in Alaska.

Epidemiology of HAV in Alaska

HAV infection remains ubiquitous in many resource-limited settings worldwide, primarily due to limited access to treated water and insufficient sewage systems [11]. In Alaska, rural communities have historically faced large cyclic hepatitis A epidemics that typically recurred every 10–12 years [4]. A serosurvey conducted in the 1980s utilizing 4030 residual sera from the Alaska Area Specimen Bank revealed that seroprevalence, the percentage of the population with antibodies to HAV (anti-HAV), was high among Alaska Native people overall (49%) but differed by age group, with increasing seropositivity observed with increasing age [4]. Alaska Native people born before 1945 had the highest HAV seroprevalence at 85% [4]. During 1990–1998, incidence of HAV infection among American Indian/Alaska Native (AI/AN) people was 6.5 times the national average [12]. Since 2000, after the implementation of widespread HepA vaccination, no new epidemics of HAV infection have occurred in Alaska (Fig. 1) [6,7,13]. Of the eight cases of HAV in Alaska during 2018–2024, three (38%) occurred in persons who acquired HAV while traveling outside of the U.S., two (25%) occurred in persons who did not travel outside of the U.S., and three (38%) had unknown travel status; only one (13%) had evidence of vaccination (Table 1). A similar published review of surveillance data during 2008–2022 showed that 70% of HAV cases in Alaska were acquired out of state and 7% of cases were among previously vaccinated individuals, showing vaccination efforts have been successful in the state and travel to high-incidence areas is still a predominant risk factor for residents of Alaska [6,14].

Fig. 1.

Reported hepatitis A cases in Alaska — 1973–2024.

Table 1.

Total reported cases of hepatitis A in Alaska by year 2018–2024.

Year	Total no. of acute hepatitis A cases	Incidence per 100,000
2018	2	0.27
2019	2	0.27
2020	0	0.00
2021	1	0.14
2022	2	0.27
2023	0	0.00
2024	1	0.13

Conversely, in the contiguous 48 U.S. states, HAV outbreaks resurged starting in 2016 and peaked in 2019 [2,15]. Data from the National Notifiable Disease Surveillance System show a 2.8-fold rise in HAV rates during 2016–2020, with the highest rates among adults aged 30–49 years [12]. While AI/AN individuals experienced the highest rates of HAV infection during the 1990s, the most recent resurgence has been driven by higher rates among non-Hispanic White individuals [12]. Homelessness and drug use were frequently reported risk factors during 2016–2020 [12,15].

HepA vaccine effectiveness studies in Alaska

Pre-licensure studies

During 1950–1997 in Alaska, periodic outbreaks of HAV infection impacted thousands of people in rural communities and often spilled over into larger urban centers [9]. After a period of low HAV case numbers in Alaska during 1979–1985, an outbreak of hepatitis A began in 1986, with two notable peaks in incidence during 1989 and 1993 (Fig. 1) [4]. As part of the response at that time, HAV immune globulin was administered to household contacts of persons testing HAV positive, but it was not enough to halt these epidemics, as protection from immune globulin quickly wanes [9]. Given the public health challenge posed by these HAV epidemics in Alaska, pre- and post-licensure HepA vaccine studies were performed starting in the 1990s in Alaska. One of the first HepA vaccine studies in Alaska involved 163 Alaska Native children aged 3–6 years and 144 Alaska Native and non-Native adults who received a 3-dose series of an inactivated HepA vaccine (Havrix, GlaxoSmithKline) [5]. Children were randomized to receive 360 ELISA units (EL.U) at either 0, 1, and 2 months; 0, 1, and 6 months; or 0, 1, and 12 months; and all adults received 740 EL.U at 0, 1, and 6 months [5]. One month after the first dose, 96% of children and 90% of adults achieved protective levels of anti-HAV > 20 mIU/ml, with 100% of children and adults achieving protective levels after the third dose [5].

To further evaluate protection offered by HepA vaccines and reduce the number of doses needed to complete the series, a study comparing two doses of 1440 EL.U of inactivated HepA vaccine (Havrix, GlaxoSmithKline) was conducted among hospital employees in Alaska who were randomized to receive this vaccine by either a jet injector or traditional intramuscular (IM) injection [8]. This study was also designed to assess the rapidity of the immune response after the first dose of HepA vaccine by testing each participant for anti-HAV at 15, 30, and 210 days after vaccination [8]. At 15 days post-vaccination, 80% of participants receiving vaccine using the jet injector and 71% of participants receiving vaccine using IM injection achieved protective anti-HAV levels > 20 mIU/ml, suggesting that one dose of HepA vaccine shortly after a known exposure could be a viable alternative to HAV immune globulin regardless of administration method [8].

Given the success of prior HepA vaccine trials in Alaska and the need to slow HAV transmission, another HepA vaccine trial was initiated in three high incidence regions of Alaska directed at stopping an ongoing epidemic [9]. At the start of the study in 1993, the vaccine was not yet licensed and was in short supply from the manufacturer. Therefore, only one dose of inactivated HepA vaccine (640 EL.U) was offered, and the target population was limited to people aged < 40 years and, in some cases, seronegative persons ≥ 40 years who resided in regions where the epidemic was actively occurring [9]. In total, 4930 people from 25 communities in these three regions of Alaska received one dose of inactivated HepA vaccine [9]. Among communities that achieved > 80% vaccination coverage (the level thought to be needed to prevent outbreaks), the outbreak ceased within 2 months of vaccination efforts [9,16]. This vaccine trial showed the effectiveness of one dose of inactivated HepA vaccine in providing protection and controlling an outbreak when community vaccination levels are high. Across all pre-licensure HepA vaccine studies conducted in Alaska, no adverse events were reported aside from minor pain and swelling at the injection site observed in some participants [5,8,9].

Post-licensure studies

When a HepA vaccine was initially licensed in 1995, it was only approved for use in children ≥ 2 years, and evidence for vaccine efficacy among infants and young children was lacking [2]. To assess the safety and effectiveness of HepA vaccine in children < 2 years, a randomized clinical trial in 248 Alaska Native and children of other racial groups was conducted in Anchorage during 1996–2001 [17]. Each child received two 720 EL.U doses of inactivated HepA vaccine (Havrix, GlaxoSmithKline) at either 6 and 12 months of age, 12 and 19 months of age, or 15 and 21 months of age [17]. Participants were further stratified by the presence or absence of anti-HAV in the mother at the time of birth, as there was concern that exposure to maternal antibodies could blunt the vaccine response in young infants. Findings from this study showed that all children vaccinated at 12 and 15 months of age and 15 and 21 months of age were seropositive 7 months after vaccination, prompting the ACIP to recommend lowering the minimum age for HAV vaccination to 12 months of age [2,17]. This study also found that among infants vaccinated at 6 and 12 months of age, the percent seropositive and mean antibody level achieved after the 2-dose series was significantly lower than those vaccinated at ages ≥ 12 months, suggesting that the presence of maternal antibodies did interfere with the vaccine response [2,17]. As in pre-licensure studies, no adverse events were reported aside from minor pain and swelling at the injection site observed in some participants [17].

In 1996, the State of Alaska Department of Health recommended all children ages 2–17 years receive HepA vaccine, which they provided at no charge to uninsured individuals. In 2001, the State of Alaska mandated HepA vaccination for school entry and, in 2006, updated their vaccination recommendation to include all people aged ≥ 12 months based on CDC guidance.

HAV long-term immunogenicity studies in Alaska

Two long-term immunogenicity studies that have tracked cohorts of children for over 20 years following initial HepA vaccination have been conducted in Alaska. In the first study, 144 children ages 3–6 years received three 720 EL.U doses of inactivated HepA vaccine (Havrix, GlaxoSmithKline) [5]. After completion of the initial vaccination series, serologic testing to assess the level of anti-HAV was performed every 2–3 years [10,18–20]. At 10 years after initiating vaccination, serologic testing was performed on 67 children; all maintained protective anti-HAV levels ≥ 20 mIU/ml [18]. However, at 17 years post initial vaccination, 54 of 58 children (93%) maintained protective anti-HAV levels ≥ 20 mIU/ml [19]. At 20 years post initial vaccination, serologic testing was performed on 52 children, and 46 of these persons (89%) maintained protective anti-HAV levels ≥ 20 mIU/ml [20]. Finally, at 25 years post initial vaccination, serologic testing was performed on 43 children, and 35 (81%) maintained protective anti-HAV levels ≥ 20 mIU/ml [10]. A survival analysis using participant data from all time points predicted that 79% of participants maintained protective anti-HAV antibody levels ≥ 20 mIU/ml at 25 years post vaccination [10].

In the second study, 183 children in three study groups received two 720 EL.U doses of an inactivated HepA vaccine (Havrix, GlaxoSmithKline) at 6 and 12 months (group 1), 12 and 18 months (group 2), or 15 and 21 months (group 3) of age [17]. Serologic testing was performed at 3, 5, 7, 10, 12–14, 15–16, 18, 20, and 23 years of age and children were stratified based on if they were born to a mother testing positive for HAV antibodies [14,21,22]. All children in groups 2 and 3 maintained seropositivity through age 10 years; however, by age 15–16, only 88% of children in these groups remained seropositive [21]. At age 20, 77% of persons in groups 2 and 3 maintained protective anti-HAV levels > 20 mIU/ml [22]. At 23 years of age, 86% of persons in groups 2 and 3 maintained protective anti-HAV levels > 20 mIU/ml compared to 11 out of 18 (61%) persons vaccinated at 6 months of age [14]. Furthermore, the geometric mean concentration (GMC) of anti-HAV was significantly higher in participants whose mothers tested negative for anti-HAV at enrollment compared to those born to mother a who was anti-HAV positive at enrollment [14]. The findings from these two studies highlight the need for thoughtful evaluation of the HepA dosing schedule when developing vaccination policy.

Discussion and recommendations

The findings from Alaska studies suggest that widespread vaccination can reduce community transmission and individuals immunized as children are likely to maintain long-term immunity against HAV. Surveillance data have shown vaccination efforts have been successful in eliminating transmission in the state and travel to high-incidence areas is still a predominant risk factor for residents of Alaska [6,14]. HepA vaccination remains the most important tool for hepatitis prevention and postexposure prophylaxis against HAV. Additional HepA vaccine studies to assess duration of immunity beyond 25 years for adults vaccinated as young children will be needed to determine the necessity of booster doses [14].

In addition to the HepA vaccine studies performed in Alaska, a study conducted in Belgium that followed 232 children aged 1–11 years who were vaccinated with a two-dose dual HepA (720 EL.U) and HepB vaccine found that 98% of individuals maintained anti-HAV levels ≥ 15 mIU/ml at 20 years post-vaccination [23,24]. Another study from Argentina that followed children aged 12–59 months who were vaccinated with two-dose HepA vaccine found that all persons maintained anti-HAV levels ≥ 20 mIU/ml at 14–15 years post vaccination [25]. Based on these data, modeling estimates predicted that at 30 years post vaccination, 88% of people vaccinated would remain protected against HAV [25]. Several other long-term HAV vaccine immunogenicity studies in adolescents and adults have also demonstrated sustained protection against HAV as assessed up to 10–20 years after vaccination, with modeling estimates showing 95% protection with anti-HAV levels ≥ 20 mIU/ml out to 25–33 years [26–29].

However, more studies are needed to determine the duration of protection offered by HepA vaccines initially administered in early childhood, especially for individuals that are now 30 years out from vaccination. Additionally, more studies are needed to determine whether booster doses may be needed for those traveling to high-incidence areas or areas where HepA vaccines are not routinely administered. Considering HAV is no longer endemic in Alaska, prevention efforts should prioritize maintaining high levels of HepA vaccination coverage, particularly among young children [6,7,30]. Furthermore, HAV surveillance data should continue to be analyzed to identify any vaccination coverage gaps [30]. Adults in Alaska who have never been vaccinated against HAV should be offered the HepA vaccine if they are at increased risk of infection or increased risk of severe disease from infection [2]. Improving access to clean drinking water and sanitation services is important in some rural areas in Alaska, as well as among people experiencing homelessness and those living in congregate settings [6,30].

Findings from this review have several limitations. First, the impact of HepA vaccination achieved in Alaska may not be generalizable to other settings related to both the level of HAV disease endemicity before vaccination and the high population immunity achieved through vaccination campaigns. No differences in HepA vaccine response have been observed between Alaska Native and non-Alaska Native adults and children [5,8,17]. Second, variation in the specific HepA vaccine products used across studies may contribute to differences in response rates and antibody titers, as well as duration of immunity. Finally, loss to follow-up in long-term immunogenicity cohorts could have introduced bias and limited the precision of estimates regarding the duration of protection.

Conclusions

HepA vaccination has dramatically reduced hepatitis A in Alaska since the mid-1990s after the State of Alaska recommended childhood vaccination, with no epidemics detected after 2000. Given the challenges some Alaskans face in accessing treated water and sanitation systems, HepA vaccine administration is paramount. Evidence shows HepA vaccines provide protection for at least 20 years for most people. However, further evidence of vaccine protection beyond 25 years will be important to inform the current immunization schedule. This work underscores the foundational research on HepA vaccination conducted in Alaska and emphasizes the importance of sustaining high levels of HAV immunity within the population.