Hepatitis A Vaccines

History of Hepatitis A Disease

Contagious jaundice was initially recognized independently in Europe—by the Greeks at the time of Hippocrates—and in Asia, by the Chinese ; however, the earliest recorded outbreaks of jaundice that appear epidemiologically to have been hepatitis A occurred in Europe in the 17th and 18th centuries. Early in the 20th century, Cockayne concluded that sporadic and epidemic forms of jaundice were probably manifestations of the same disease, and McDonald postulated that a virus might be involved. Complementing these insights, epidemic, undifferentiated hepatitis has been a military problem for centuries, with major outbreaks occurring among troops from many nations from all sides during both of the 20th-century world wars.

The first scientific evidence that hepatitis A was an enterically transmitted infection was obtained during World War II from studies among experimentally infected volunteers. In a classical series of experiments, volunteers in whom infectious hepatitis had developed were protected from subsequent challenge with the same virus and from infectious material obtained from a separate outbreak. ^, Havens and colleagues also demonstrated that intramuscular injection of pooled normal human immunoglobulin could prevent or attenuate the disease, and the practice was rapidly adopted. During an epidemic among American soldiers near the end of World War II in the Mediterranean theatre, more than 2700 American soldiers were administered immunoglobulin, which reduced the incidence of disease by 86% among immunized troops.

By the end of World War II, volunteer studies had clearly established that infectious hepatitis was enterically transmitted and caused by a filterable agent—presumably a virus—that was relatively heat-stable but could be inactivated by chlorine. In addition, infectious hepatitis (hepatitis A) was known to be distinct from serum hepatitis (hepatitis B) in mode of transmission and etiology. The World Health Organization’s First Expert Committee on Viral Hepatitis adopted this differentiation in 1952. Fecal samples collected from studies during the 1950s were critical in the identification of the etiologic agent of the disease by electron microscopy in 1973 ( Fig. 26.1 ).

Why the Disease Is Important

An estimated 159 million acute hepatitis A cases and 39,000 deaths occurred in 2019, with 2.3 million disability-adjusted life years related to hepatitis A. The burden of disease in 2019 was not equally distributed worldwide. Overall, 66% of acute hepatitis A cases and 97% of hepatitis A deaths occurred in low-income countries and low-middle-income countries. In absolute numbers, South-East Asia had the greatest number of hepatitis A cases (42 million) and deaths (23,711; 60% of the total number of deaths). In terms of rates, hepatitis A disease incidence was highest in the African Region (3,714 cases per 100,000 population) and hepatitis A-related mortality was highest in South-East Asia (1.18 deaths per 100,000 population).

Clinical Description

Hepatitis A is an acute infection of the liver. The incubation period ranges from 15 to 50 days after exposure with the mean incubation period being approximately 28 days. ^, The average incubation period is shorter among patients who acquired hepatitis A virus (HAV) infection by parenteral transmission from contaminated blood products compared with those infected orally, and among those with a higher infectious dose.

Infection with HAV, as evidenced by the detection of HAV-specific immunoglobulin M (IgM) antibody in serum, may produce a wide spectrum of disease outcomes ranging from inapparent (asymptomatic, without elevation of serum aminotransferase levels), to subclinical (asymptomatic, with elevation of serum aminotransferase levels), to clinically evident (with symptoms).

The clinical symptoms of acute hepatitis A are indistinguishable from those caused by other forms of viral hepatitis. HAV ribonucleic acid (RNA) is shed in large amounts in the stool as well as being detectable in the blood during the incubation period. The onset of the prodromal period, particularly in older children and adults, can be abrupt and is characterized by increasing fatigue, malaise, anorexia, fever, myalgias, dull abdominal pain, nausea, and vomiting. Atypical symptoms are more common in children who may experience diarrhea or, less commonly, upper respiratory symptoms including cough and coryza. Clinically typical manifestations of hepatitis will appear several days to a week following the onset of the prodromal period and relate to cholestasis. These include darkening of the urine (bilirubinuria) which is often followed by jaundice (yellow discoloration of the sclera, skin, and mucus membranes) and pale-colored stools in addition to hepatomegaly and tenderness. Pruritus, also caused by cholestasis, occurs in less than 50% of patients, but may be severe.

The major determinant of clinical hepatitis is age. Only 10–50% of infections acquired before the age of 5 years are symptomatic, whereas 70–95% of infected adults have symptoms. The likelihood of jaundice increases linearly with age, being rare among young children but experienced by the majority of adults with hepatitis A. ^, The duration of illness varies, but most patients feel better within several weeks. Resolution of prodromal symptoms is common during the icteric phase of the illness. HAV RNA shedding in the stool peaks just prior to liver injury (the inflammatory process) and can persist for up to 3 months from the onset of infection. ^, Prolonged elevated aminotransferase (lasting >14 weeks) occurs in <10% of individuals. HAV IgM becomes positive around the time of initial symptoms and persists for 3–9 months. As the illness progresses, it is gradually replaced by immunoglobulin G (IgG). HAV RNA viremia becomes undetectable in self-resolving cases within 3 weeks of the onset of symptoms and prior to normalization of alanine aminotransferase (ALT). The duration of HAV viremia can be almost 100 days. Even in prolonged hepatitis A infection or relapse (which occurs in around 10% of cases and can be biochemical or clinical), symptoms often resolve within 6 months. Recovery is universal in these cases, with immunity being lifelong. Chronic HAV infection has not been identified.

Complications

Beyond cholestatic jaundice and associated pruritis, ^{, ,} extrahepatic manifestations, which are rare, of HAV infection include hematological, acute kidney failure, pleural or pericardial effusion, reactive arthritis and other immune complex related phenomena, acute pancreatitis and cholecystitis and neurological manifestations ^, as listed in Table 26.1 . ^, Complications have been reported among pregnant women with acute hepatitis A infection, including premature rupture of membranes or placental separation. In addition to these complications of HAV infection, HAV exposure may be associated with protection from atopy, a mechanism supporting the hygiene hypothesis of atopy and asthma.

The overall case-fatality ratio (CFR) is low but varies according to the population studied. Among hospitalized patients with hepatitis A in Australia, the mortality rate was estimated to be 0.14%. In the large 1988 Shanghai epidemic that involved primarily adolescents and young adults, there were 47 deaths (0.015%) recorded among the 310,746 diagnosed cases. In the United States, during communitywide outbreaks, CFRs have ranged from 0.1% to 0.7%, —from virtual absence in healthy children to up to more than 2% in older adults. All-age mortality for hepatitis A in the United States ranged between 0.7% and 1.0% during 2013–2016 among reported cases with complete information on death. Fulminant hepatitis A disease is acute liver failure with encephalopathy within 8 weeks of symptom onset and is the most serious consequence of HAV infection. It occurs in an estimated 1.3% of cases and is more common in adults, although it can also occur in children. ^{, ,} Host factors associated with increased risk include those with chronic liver disease, other viral hepatitis coinfection—though hepatitis C impact may be variable, the use of hepatotoxic medications such as acetaminophen/paracetamol, and being of older age (>50 years). ^{, ,} Once hepatitis has become fulminant, mortality is high at 60–80%. ^{, ,} Interestingly, fulminant hepatitis A is associated with low HAV RNA viremia, perhaps indicating a strong immune response. In addition, low initial creatinine and serum ALT are associated with poorer outcome in fulminant HAV infection.

Diagnosis

Hepatitis A virus infection and disease is clinically indistinguishable from other forms of acute viral hepatitis, so diagnosis requires serologic detection of HAV-specific IgM in a single acute-phase serum sample ( Table 26.2 and Fig. 26.2 ). The HAV-specific IgM antibody generally is detectable 5–10 days prior to symptom onset, persists, then declines to undetectable levels within 6–12 months in most cases. It has very high sensitivity and specificity for current or recent infection, is inexpensive, and is widely available in most countries. ^, ( Fig. 26.2 ). Serologic assays can be initially negative in up to 10% of patients who are tested soon after symptom onset and testing should be repeated if hepatitis A is suspected clinically, particularly in the setting of an ongoing outbreak. ^, Molecular HAV RNA detection may be more sensitive in this early period. ^, In addition, cases of positive test results for IgM anti-HAV more than 1 year after infection have been reported. Furthermore, IgM detection in the absence of symptoms can reflect asymptomatic infection or a false-positive result, reflecting a low positive predictive value of the test when used to test asymptomatic persons. ^{, ,} Biochemical evidence supporting a diagnosis of acute hepatitis A disease consists of elevated serum bilirubin and hepatic transaminases, including ALT, aspartate aminotransferase (AST), alkaline phosphatase, and γ-glutamyl transpeptidase. Elevations in AST and ALT levels occur most consistently and may precede the appearance of symptoms by a week or more ( Fig. 26.2 ). Except for patients with relapsing or cholestatic hepatitis A, serum bilirubin and aminotransferase levels usually normalize within 2–3 months after illness onset.

A desire to monitor vaccine-induced protective immune responses prompted development of several in vitro assays for detection of HAV-neutralizing antibodies and serologic assays able to differentiate HAV immunity acquired after infection from that acquired following vaccination. Several diagnostic assays for the detection of HAV antibody in oral fluid have been developed, including rapid assays to support population-based seroprevalence studies, ^, and have recently been integrated into national outbreak responses.

Other tests are rarely used for the diagnosis of HAV infection (see Table 26.2 ). Viral detection assays generally have not been useful because wild-type HAV is extremely difficult to isolate in cell culture and the virus grows slowly, usually requiring weeks or months. Because virus shedding peaks before the onset of clinical illness, antigen detection systems usually are insufficiently sensitive to detect HAV in stool samples. Polymerase chain reaction (PCR) techniques have been useful in certain clinical, epidemiologic, and environmental studies. ^{, ,} Commercially available serologic tests that measure total anti-HAV are used most often in epidemiologic investigations or in determining susceptibility to HAV infection as both natural infection and vaccine-acquired immunity will result in the presence of total anti-HAV (as IgG antibody).

Treatment

No specific therapy is available for hepatitis A, and management is supportive. In most patients, hospital admission is not necessary. Activity, including exercise, should not be restricted among healthy patients who can tolerate it, as there does not appear to be an adverse impact on the course of illness. Medications, particularly those metabolized by the liver or that are potentially hepatotoxic, should be used with caution because their half-life may be prolonged or promote additional insult to the liver. Alcohol should be avoided. Hospitalization may be necessary for patients who become dehydrated from vomiting and is necessary for those who develop fulminant hepatitis.

Hepatitis A complicated by cholestasis results in pruritus (itching), which can be bothersome. In addition to general measures, the anion exchange resin cholestyramine can be useful. Corticosteroids are not normally indicated and should be used with caution, although have been described for use in specific instances. ^, In the rare event of fulminant hepatitis with hepatic failure, hospitalization with intensive care is indicated and though prognosis is worse than that of other causes of fulminant liver failure, most patients survive. ^, Liver transplantation is the only definitive treatment in fulminant hepatitis for those who fail to recover with supportive care; however, clear criteria for transplant remain elusive. ^{, , ,} Persistent HAV infection and loss of acquired immunity leading to reinfection has been demonstrated in some transplant recipients. ^,

Virology

HAV is a member of the Picornaviridae family, which includes the enteroviruses and rhinoviruses of humans. While HAV resembles enteroviruses in most morphologic and physical aspects, owing to several unique features, HAV has been placed into its own genus, Hepatavirus . ^, The HAV genome is composed of a single-stranded linear RNA molecule of 7478 nucleotides (strain HM175) ( Fig. 26.3 ). It has positive polarity, a relatively long 5′ untranslated region (UTR) of 735 nucleotides, followed by a single, long open reading frame of approximately 6681 nucleotides coding for a polyprotein of 2227 amino acids, in turn followed by a short 3′ UTR ending with a virus coded poly(A) tail. The HAV structural proteins are coded by the 5′ third of the open reading frame and the nonstructural proteins coded by the remainder. The 5′ end of the HAV genome does not have a cap structure but instead has a small, covalently bound, virus-coded protein termed VPg (3B protein). The 5′ UTR includes an internal ribosomal entry site for cap-independent translation. ^, Translation begins at one of two in frame AUG codons at nucleotide position 735 or 741. The polyprotein is divided into three parts, P1, P2, and P3. The four capsid proteins, VP1, VP2, VP3, and VP4, are coded by the first 2373 nucleotides (P1) and the nonstructural proteins by the remainder (P2 and P3). The gene order and protein function of HAV are similar to the other picornaviruses. However, there are differences in the details of the protein cleavages, the size of the capsid proteins, myristoylation at the N-terminus, and the inclusion of the small VP4 in the virion particle.

The 2A protein of poliovirus has proteinase activity and makes the VP1/2A cleavage. However, the 2A (a.k.a. pX) of HAV is not required for replication, but at least the N-terminus is needed for particle assembly ^, and the C-terminus is important for production of the enveloped form of HAV. The 2B and C proteins are believed to be involved in replication. Mutations leading to cell culture adaptation and attenuation in animals have been mapped to these regions. Protein 3C is a protease responsible for all proteolytic cleavages of the HAV polyprotein except the VP0 cleavage. ^{, ,} Protein 3D is a polymerase responsible for the replication of the genomic RNA.

HAV is more resistant to heat than other picornaviruses are. While HAV may be incompletely inactivated (depending on the conditions) by exposure to 60°C for 10–12 hours, complete inactivation has been reported after heating for 4 minutes at 70°C, 5 seconds at 80°C, and virtually instantly at 85°C. HAV can be reliably inactivated by autoclaving (121°C for 30 minutes). HAV may survive extended periods in shellfish, water, soil, and marine sediment. Outbreaks of hepatitis A virus infection have been reported following ingestion of partially cooked shellfish, suggesting that the usual steaming conditions used to cook shellfish may be inadequate to destroy the virus. The virus is resistant to most organic solvents and detergents and a pH as low as 3. ^, HAV can be inactivated by many common disinfecting chemicals, including hypochlorite (bleach), and quaternary ammonium formulations containing 23% HCl found in many toilet bowl cleaners. Photoinactivation of HAV in solution by the addition of porphyrins has been demonstrated. Currently, licensed vaccines are inactivated by 1:4000 formalin at room temperature for at least 15 days; this exceeds complete inactivation by at least threefold.

There is only one HAV serotype throughout the world. People who were infected by HAV in one part of the world are not susceptible to reinfection in another part of the world, and immunoglobulin prepared in a variety of developed countries or vaccines developed from single strains of HAV protect travelers throughout the world.

One vaccine approved in the United States was developed from a genotype I virus originally isolated from an Australian patient (HM175); another vaccine was derived from a genotype III virus originally isolated from a Costa Rican patient (PA21). Although the two vaccine strains differ by 16.8% in the nucleotide sequence of the structural protein coding region, no significant antigenic differences were observed in a cross-cross neutralization assay, and both viruses reacted nearly identically with a panel of 18 monoclonal antibodies. ^,

The antigenic composition of the HAV capsid has been extensively analyzed through binding studies of neutralizing monoclonal antibodies and neutralization escape mutants. Neutralization epitopes of HAV are contained primarily in VP1 and VP3. However, neutralizing monoclonal antibodies do not recognize either oligopeptides predicted to contain neutralization epitopes nor denatured individual viral capsid proteins. In addition, antibodies raised against these synthetic oligopeptides do not neutralize, suggesting that these neutralization epitopes are conformational. Binding competition assays of neutralizing monoclonal antibodies have indicated that the neutralization epitopes are in proximity on the virion surface. ^,

There are two types of hepatitis A virions: nonenveloped or “naked” and quasienveloped (eHAV). Naked virions found in feces of infected humans and nonhuman primates are formed from VP1, VP2, VP3, and VP4, with pX playing an essential role in capsid assembly but not included into virions. HAV circulating in blood of infected humans and chimpanzees is enveloped into the host cell membrane, which prevents recognition of the form of HAV by antibody in enzyme immunoassays. Enveloping of HAV with the host membrane may affect neutralization with antibody and potentially assists in spreading HAV infection in the liver. Domain pX remains attached to VP1 in eHAV. These virions resemble exosomes and maintain specific infectivity in cell culture, similar to naked virions.

Infection is typically established in the host by naked virions; however, spread of infection in the host likely involves eHAV. T-cell immunoglobulin and mucin domain containing protein 1 (TIM1) also known as HAV cellular receptor 1 protein (HAVCR1), initially reported to be a receptor for HAV, was recently found to be nonessential for HAV entry. The initial eHAV uptake by cells occurs by mechanisms similar to those used by exosomes. Both virion types use gangliosides as essential endosomal receptors. eHAV enters cells via an endolytic mechanism. Its membrane is removed slowly, exposing capsid to the neutralizing antibody inside an endosomal compartment. The naked virion enters cells rapidly and is not affected by postendocytic neutralization. ^, An inverse association was identified between HAV infection and atopy in humans, and there has been the suggestion that this could be related to the effect of HAV infection on TIM1-induced T-cell differentiation. Unlike many viruses that activate the CD4+ CD25+ regulatory T-cells (Tregs), HAV temporarily impairs Treg functions during acute infection. Direct binding of HAV to TIM1 on Treg inhibits the cell functions. The transitory block of Treg may lead to removal of pathogenic T cells, providing protection against development of autoimmune and allergic states. After receptor binding and entry, HAV follows the general replication strategy of other picornaviruses in uncoating, translation, RNA replication, and assembly. Replication of HAV is intimately related to the cytoplasmic membranes, and proteins 2C and 2BC have been shown to interact with and induce rearrangement in these membranes.

The features of HAV replication in cell culture also distinguish it from many other picornaviruses, and these characteristics are important for vaccine production; for example, HAV is cultured in human lung fibroblast cells, MRC-5, using medium-perfused bioreactors for production of inactivated hepatitis A vaccine, VAQTA. The virus generally grows slowly to low titers. Most HAV strains do not significantly interfere with host transcription or translation, and the virus does not cause a cytopathic effect or kill the cells in which it is growing. Instead, the virus readily establishes persistently infected cells, and the virus remains largely cell associated. A few cells from culture-adapted viruses that grow rapidly exhibit a cytopathic effect and cause cell death through apoptosis.

Many HAV strains have been isolated in cell culture directly from clinical material, although the procedure may take several weeks or even months of adaptation to in vitro growth. A cell line derived from human hepatoma cells, Huh-7 cells, seems to have the capacity to grow field isolates of HAV. In addition, cells of nonprimate animal origin have now been shown to support at least limited growth of HAV.

Cell culture of HAV has been used to alter the phenotype of the virus primarily for growth characteristics and attenuation of virulence. Attenuated strains of HAV have been selected by multiple tissue culture passages, and cold adaptation has been achieved by passage at reduced temperature. Some mutations responsible for these altered phenotypes have been determined by molecular cloning and sequencing of the mutant and comparing its sequence with the parental strain. Mutations within the 5′ UTR, and 2B and 2C coding regions of HAV RNA are associated with enhanced virus replication in vitro . ^,

HAV is known to infect humans, at least chimpanzees among the great apes, and some species of monkeys. The most extensively characterized models are the chimpanzee and two New World monkeys, tamarins and Aotus (owl) monkeys. ^{, ,} Transmission of HAV to primate handlers is well documented; however, it has not been determined if these monkey isolates are true simian HAVs or human viruses that have infected monkey colonies where they have persisted and adapted. Limited HAV replication has been demonstrated in guinea pigs. Therefore, while HAV may be transferred to nonhuman primates and even lower-order animals, it is not clear if any of these species serve as a reservoir for HAV in the environment, which could then be a source of human infections.

Pathogenesis as It Relates to Prevention

HAV is generally transmitted by the fecal–oral route, and this acid-resistant virus can survive passage through the stomach. In tamarins and chimpanzees, approximately 10 intravenous doses were required to infect the same species by the oral route. The primary site of HAV replication is in the liver, although experimental data in chimpanzees suggest that HAV may also replicate in the oropharynx. ^, HAV has been identified by immunofluorescence in the epithelial cells of the intestinal crypts of the jejunum and ileum of experimentally infected monkeys. ^, The period of viremia has been measured by a sensitive reverse transcriptase–polymerase chain reaction in 13 naturally acquired human cases and five experimentally infected chimpanzees: HAV RNA was detected an average of 17 days before the peak alanine aminotransferase (ALT) level and persisted an average of 79 days after the peak ALT. The average total duration of viremia was 95 days (range: 36–391 days). Although other organs might be seeded by the viremia, HAV, like many other picornaviruses, seems to be highly organ-specific, and the primary pathologic process in hepatitis A is restricted to the liver. Virus is shed from infected liver cells into the hepatic sinusoids and the bile canaliculi, passes into the intestine, and is excreted in the feces, where it may be found in high titers early in the infection.

Because HAV is generally not cytopathic in cell culture, the pathologic findings in experimental animals and humans show little hepatocyte damage at the peak of viral replication. Immune mechanisms, in particular cell-mediated immune responses, have been postulated to explain the hepatic injury. ^, In contrast, circulating antibodies are probably more important in limiting spread of virus to uninfected liver cells, which, in combination with specific T cells, are responsible for termination of the infection. As HAV is a positive strand RNA genome virus that goes through a double-stranded intermediary during its replication cycle, infection by HAV should be a strong inducer of type I interferons. HAV uses several molecular mechanisms to disrupt early innate immune responses controlling induction of interferon synthesis, ^, which results in a limited type I interferon response in the liver infected with HAV. Experimental animal models showed that HAV does not noticeably induce expression of interferon-stimulated genes (ISGs) despite the approximately 100-fold greater abundance of HAV RNA in the liver than during acute infections with other hepatitis viruses. ^, The cellular helicases, RIGI and MDA5, and Toll-like receptor 3 (TLR3) are pattern recognition receptors that are activated by double-stranded RNA (dsRNA) and initiate the interferon signaling cascade. Many viruses have evolved mechanisms to evade the interferon system. For example, the hepatitis C virus (HCV) protease cleaves RIGI, thus disrupting downstream signaling. It was recently shown that HAV has a mechanism that is similar to HCV. The 3ABC precursor of the HAV 3C protease is targeted by the transmembrane region of protein 3A to the mitochondrial membrane, where it then cleaves the mitochondrial antiviral signaling protein, MAVS. The cleavage of MAVS in turn disrupts the downstream interferon pathway and inhibits the production of interferons and interferon-induced antiviral proteins.

In addition to the 3ABC intermediate, other products of incomplete processing of the HAV polyprotein play an important role in mitigating interferon response. For example, the 3CD intermediate disrupts TLR3 signaling and, consequently, interferon production.

Although liver damage (as measured by ALT elevations) begins at about the same time that circulating antibodies become detectable, there are no data suggesting that the pathology is antibody-mediated but is more likely from cytotoxic T lymphocytes. Although passive immunization with immunoglobulin can provide complete protection against infection, no data exist suggesting that already infected patients can be treated by infusion of antibodies. The effectiveness of immunoglobulin also suggests that mucosal immunity is not required for prevention of HAV infections. ^,

Molecular Epidemiology

HAV is genetically heterogeneous. Originally, HAV was classified into seven genotypes using a 168-nucleotide fragment of the HAV genome containing the VP1/P2A junction, but it was recently reclassified into six genotypes, I to VI, based on sequences from the VP1 region. Clear differences in clinical outcomes among the genotypes are not established. Despite multiple genotypes of HAV, there is one recognized serotype. Genotypes I, II, and III circulate among humans, and genotypes IV, V, and VI infect simians. ^, Genotypes are divided into subtypes A and B. Geographic distribution of HAV genotypes and subtypes is not uniform. Genotype I has a worldwide distribution, with subtypes IA and IB frequently cocirculating. Subtype IA is prevalent in South and North America, Europe, Asia, and Africa, while subtype IB is predominant in the Middle East and South Africa. Recent evaluation, however, suggests that subtype IB is more abundant in South America than previously thought. Genotype II seems to have a West African origin, but it is not frequently detected. Subtype IIA was recently detected in Central Africa. Genotype III circulates globally; however, its prevalence varies among geographic regions. ^, Over the past two decades, an increase in subtype IIIA infections has been reported in Korea, Russia, and Estonia. Circulation of more than one subtype and genotype in certain geographic regions provides an opportunity for coinfection and recombination. Recombination between cocirculating HAV subtypes has been reported.

HAV genetic heterogeneity is used for the identification of HAV strains and for outbreak investigations. The detection and sequencing of HAV RNA from water, food, and blood or saliva of infected individuals provide important information for tracing HAV strains and identifying the source of hepatitis A outbreaks. ^, Molecular investigations are mainly conducted using short HAV genomic regions, usually VP1/P2A junction. However, analysis of whole-genome sequences showed that the VP1/P2A sequences may be shared by different HAV strains and that more than one closely related HAV strain may be involved in a single foodborne outbreak. Exposure to several HAV strains has been reported during outbreaks associated with person-to-person transmission in endemic regions.

Genetic characterization of HAV strains collected during outbreak investigations has revealed important trends in HAV transmission in different epidemiologic settings. For example, identification of a few, large monophyletic clusters of the subtype IA HAV strains and sharing of these strains during outbreaks among men who have sex with men (MSM) from several countries in Europe indicates infrequent introductions of HAV strains into broad MSM networks capable of sustaining the introduced HAV variants for a prolonged period. In contrast, the presence of many unique HAV variants and small monophyletic clusters of subtypes IB and IIIA among travelers returning from endemic countries emphasizes introduction of numerous HAV strains that have not spread broadly in Europe. ^, Detection of subtype IIIA among injection drug users in developed countries was interpreted as a frequent introduction of HAV to these communities through contaminated drugs originating in Central and South Asia where this subtype is prevalent. ^,

Worldwide Disease Patterns and Population Immunity Against Hepatitis A Virus

Hepatitis A occurs worldwide, but major geographic differences exist in endemicity and epidemiologic patterns of hepatitis A incidence and anti-HAV antibody prevalence ( Fig. 26.4 ); these patterns are a result of environmental (hygienic and sanitary) and socioeconomic conditions. Hepatitis A also exhibits seasonality, which has been documented in some Asian countries.

Anti-HAV IgG antibodies can be an indication of past infection or of vaccine-induced immunity and likely persist for life. Endemicity is defined as relating to the age at midpoint of population immunity (AMPI), which is the youngest age at which half of the birth cohort has serologic evidence of previous exposure to HAV. As the AMPI increases, the endemicity level of hepatitis A generally decreases, with different geographies categorized as areas of high, intermediate, low, or very low endemicity (see Fig. 26.4 ). However, determining global HAV endemicity is complex, and limited data are available on subpopulation variation of anti-HAV seroprevalence within regions and subnational areas. ^,

In general, in areas of high endemicity, represented by low-income countries (i.e., parts of Africa and South-East Asia), poor hygienic and sanitary conditions allow HAV to spread readily. Infection is nearly universal in early childhood, when asymptomatic infection predominates, and most of the population is infected before reaching adolescence, as demonstrated by the age-specific prevalence of anti-HAV antibodies. In these regions, because most adults are immune, reported disease rates in this population are low and few outbreaks occur. However, susceptible adolescents and adults in these areas are at high risk for hepatitis A. In some highly endemic countries, recent surveillance data have demonstrated increasing numbers of cases among adults with frequent outbreaks, and small seroprevalence studies have identified greater susceptibility of some children into adolescence. Differences in susceptibility to hepatitis A in low- and middle-income countries can be defined by socioeconomic status, where more affluent children living in more hygienic conditions—often urban areas—being more likely to escape HAV infection as infants and young children, leaving them susceptible to HAV infection as adolescents and adults.

In areas of intermediate endemicity, HAV is not transmitted as readily due to improved sanitary and living conditions, and the predominant age at infection is older than in areas of high endemicity. Paradoxically, the overall incidence and average age of reported cases are often higher than in highly endemic areas because high levels of virus circulate in a population that includes many susceptible older children, adolescents, and young adults who are more likely to develop symptoms with HAV infection. Person-to-person transmission in community-wide epidemics continues to account for much of the disease in these countries. Shifts in age-specific prevalence patterns that reflect a transition from high to intermediate endemicity are occurring in many parts of the world. A feature of this transitional pattern is striking variations in hepatitis A epidemiology among countries and within countries and cities, with some areas within countries displaying a pattern typical of high endemicity and others of intermediate endemicity. ^{, ,}

In high-income countries, the endemicity of HAV infection is low or very low. Few children are infected, the incidence of disease is generally low, and disease is usually seen in sporadic outbreaks and limited to high-risk groups. Population-based seroprevalence surveys show a gradual increase in the prevalence of anti-HAV antibodies with increasing age, primarily reflecting declining incidence, changing endemicity, and resultant lower childhood infection rates over time.

In countries with universal hepatitis A childhood vaccination programs, population immunity continues to increase, further reducing the risk of hepatitis A. In areas where routine vaccination of children has not been implemented, such as much of Europe, population susceptibility continues to grow.

Region-Specific Incidence and Seroprevalence Data

A 2019 systematic review of hepatitis A epidemiology in the African region found that while seroprevalence in this region remains high, there was substantial heterogeneity and some countries may be transitioning to intermediate endemicity. However, little recent data across the continent is available, with only 24% of African countries represented in this review and no recently reported data on hepatitis A hospitalization or case fatality rates.

For the Region of the Americas, a detailed description of hepatitis A epidemiology in the United States is provided below. In general, HAV seroprevalence in the United States and Canada is low. A 2020 systematic review of hepatitis A epidemiology in Latin American countries found that many countries in this region have transitioned from high to intermediate endemicity, with low seroprevalence in the southernmost countries. However, recent data were lacking for most countries. The lowest incidence of hepatitis A was reported in Brazil, Columbia, Panama, and Paraguay, where pediatric hepatitis A national immunization programs have been introduced; the highest incidences were reported in Belize, Ecuador, and Nicaragua.

A 2017 systematic review estimated HAV seroprevalence to be 63% in the Eastern Mediterranean region and 66% in the Middle East, with lowest seroprevalences in Cyprus (3%), United Arab Emirates (21%), and Kuwait (29%), and the highest prevalence in Afghanistan (99%), Iraq (96%), Somalia (96%), and Palestine (94%). However, no data were available for Bahrain, Djibouti, Libya, Oman, Qatar, and Sudan. In Iraq, hepatitis A incidence increased by an annual average of 15% from 2004 to 2016, possibly attributable to poor hygiene practices, interrupted water supplies, and population displacement in this conflict setting.

Western Europe is an area of low seroprevalence, with higher prevalence among migrants and key populations. In general, seroprevalence increases from West to East, with variable anti-HAV prevalence in Central Europe. Eastern Europe is an area of intermediate endemicity which has decreased over time. Little recent seroprevalence data are available from the Baltic States. In general, children aged 5–14 years account for most cases in the European region, and numerous recent outbreaks have occurred, both foodborne and related to men who have sex with men (MSM) communities (see below section on the Modes of Transmission and Outbreaks).

Hepatitis A is highly endemic in South-East Asia, though with considerable variation. In India, high seroprevalence has been reported among military recruits, healthcare workers, and teenagers in whom infection-induced immunity in lower-income groups equaled vaccine-induced immunity in high-income groups. While prior studies in Pakistan indicated near universal exposure to hepatitis A by age 14 years, the incidence of acute hepatitis A among adults has increased in recent years indicating an immunity gap. Nepal has reported similar trends.

In the Western Pacific Region, hepatitis A endemicity varies widely, correlating with urbanicity and socioeconomic status. Seroprevalence is low in high-income countries, and high in low-income countries. Hepatitis A incidence decreased markedly following vaccine introduction in China, with remaining discrepancies correlating with vaccination coverage and regional socioeconomic status. ^{, ,} Japan has reported very low seroprevalence. In Australia, increasing seroprevalence and declining rates of disease notification are thought to be due to increases in travel to HAV endemic regions, migration to Australia from HAV endemic regions, and hepatitis A vaccine uptake. Prior to hepatitis A vaccine introduction for infants, Mongolia experienced universal seropositivity and hepatitis A was the most common cause of acute jaundice. Little is known about hepatitis A epidemiology in the rest of the Western Pacific Region.

Epidemiology in the United States

In the United States, as a result of significant decreases in incidence, owing in large part to universal childhood vaccination, there have been decreases in morbidity and mortality among children and adolescents, resulting in increases in the average age of hepatitis A-related hospitalizations and deaths. ^{, ,} Nevertheless, from a low in 2012, the incidence of reported and estimated cases has been rising consistently, especially among white adults. Although overall hepatitis A morbidity and mortality has decreased in the United States, persons hospitalized for hepatitis A in recent years are more likely to have liver diseases and other comorbid medical conditions.

Although large national outbreaks were recognized during the 1950s, data collection for hepatitis A in the United States started in 1966 (see Fig. 26.5 ). The highest number of hepatitis A cases recorded in the United States was in 1971, with approximately 60,000 cases (incidence: 29 cases per 100,000 population). In 1995, when hepatitis A vaccine was licensed in the United States, more than 31,000 cases of hepatitis A had been reported (incidence: 12 cases per 100,000 persons), making hepatitis A one of the most frequently reported vaccine-preventable diseases. Vaccine introduction had a major effect on case incidence (see Figs. 26.5 and 26.6 ). In the period 1996 to 1999, the Advisory Committee on Immunization Practices (ACIP) recommended targeted vaccination for children at 2 years of age in states with high hepatitis A rates. ^, Incidence rates declined sharply following implementation of these recommendations. In 2006, universal vaccination was recommended in all states for all U.S. children starting at 1 year of age. The number of reported cases in the United States reached an all-time low in 2011 of 1398 cases (0.4 per 100,000 population), representing a 95.5% decline in reported cases since the first vaccine recommendation in 1996 when 31,032 cases (11.7 cases per 100,000 population) were reported. The first increase in cases since 1995 occurred in 2012 (1562 total cases) and 2013 (1781 total cases), coincident with a 2013 multistate foodborne outbreak of hepatitis A. After a slight decline in 2014, cases then increased over 850% by 2019 primarily due to widespread outbreaks resulting from person-to-person transmission reported in 31 states among people who use drugs and people experiencing homelessness. ^, In 2018, a total of 18,846 cases of hepatitis A were reported from 50 states and the District of Columbia to the U.S. Centers for Disease Control and Prevention (CDC).

Young children typically have asymptomatic or unrecognized infections, and have historically, prior to vaccine introduction, played an important role in the epidemiology of hepatitis A in the United States, serving as a major reservoir for HAV transmission. Since vaccine introduction, hepatitis A rates among children have declined more sharply than among adults and since 2009, rates among children have been less than 1.0 case per 100,000 population ( Fig. 26.7 ). In 2018, persons aged 30–39 years had the highest rate (0.98 cases per 100,000 population) and persons aged 0–9 years had the lowest rate (0.10 cases per 100,000 population).

In the United States, rates of hepatitis A among Hispanics had historically been higher than those of other racial/ethnic populations. Rates among Hispanics declined 94% from 1997 to 2007 (1.4 cases per 100,000 population); in 2014–2015, the rate was the lowest ever recorded (0.4 per 100,000). Rates among all racial and ethnic groups declined dramatically and comparably in the United States with fluctuations, however in 2017–2018 disparities became apparent with a rate increase to 1.2 cases per 100,000 population among black, non-Hispanic and further increased to 2.5 cases per 100,000 population during the following year. Among White, non-Hispanic, there was an increase to 4.3 cases per 100, 000 population from 2017 to 2018, which further increased to 6.8 cases per 100,000 in the following year, likely associated with hepatitis A among persons who use drugs ( Fig. 26.8 ). Mortality associated with hepatitis A in the United States is uncommon, however an increase in reported deaths has been observed due to the ongoing hepatitis A outbreaks. The age-adjusted death rate associated with hepatitis A among U.S. residents was 0.04 deaths per 100,000 population in 2019, double the rate of 0.02 deaths per 100,000 population in 2017.

In the United States, before hepatitis A vaccine was widely available, hepatitis A occurred in large nationwide epidemics approximately every decade. The highest rates and the majority of cases occurred in the western and southwestern states. ^{, ,} With the advent of routine vaccination of children, large communitywide outbreaks and cyclic peaks have ceased, and geographic variations disappeared. However, geographic variation has reemerged associated with ongoing hepatitis A outbreaks and the location of outbreak associated populations.

In the United States rates of HAV infection remain low in children and adolescents because of routine childhood hepatitis A vaccination. However, rates of HAV infection are higher among adults because of low adult vaccine coverage and higher HAV susceptibility. Among U.S.-born adults aged ≥20 years, HAV susceptibility prevalence (total antibody to HAV negative) was 74.1% (95% confidence interval: 72.9%–75.3%) during 2007–2016.

Person-to-Person

Person-to-person transmission by the fecal–oral route is the predominant means of HAV transmission globally. Most transmission occurs among close contacts, particularly in households and extended family settings. ^, In areas of endemic transmission, young children have the highest rates of infection and are often the source of infection for others, primarily because the majority of children infected with HAV have asymptomatic or unrecognized infections and can shed the virus in their feces for months. ^, However, in the United States, with routine hepatitis A vaccination of children, transmission now occurs primarily among susceptible adults.

In recent years, person-to-person outbreaks have been reported among extended immigrant families after members become infected when traveling to their country of origin to visit friends and relatives. ^, Outbreaks have also been reported recently among refugees and asylum seekers in Greece, Turkey, and Germany. In countries experiencing war (e.g., Sri Lanka, ^, Syria ), outbreaks have occurred among internally displaced persons, local residents, and military personnel.

Since 2017, the United States has experienced high-profile multi-state person-to-person transmission outbreaks among persons experiencing homelessness, persons using injection and non-injection drugs, and their direct close contacts. These outbreaks have become more apparent in the context of overall decreases in the background incidence of hepatitis A in the United States. These outbreaks have also resulted in a large proportion of patients requiring hospitalization (71%) and a high case fatality ratio (3%), likely associated with an older age distribution and a high prevalence of comorbidities, including chronic hepatitis B and hepatitis C. ^,

Organization-based person-to-person hepatitis A outbreaks have also been reported. Outbreaks have occurred among unvaccinated adults with developmental disabilities in group homes and are associated with poor hand hygiene, wearing diapers, and living in close quarters. ^, In 2018, Indonesia reported hepatitis A outbreaks in schools, likely spread by poor sanitation and hygiene practices in the school canteens.

In recent years, a large number of person-to-person transmission outbreaks of hepatitis A have been reported among MSM worldwide. Additionally, person-to-person hepatitis A outbreaks with no clear source of transmission were reported in Northern England in 2015.

Foodborne

Hepatitis A virus can remain infectious in the environment, allowing for common-source outbreaks and sporadic cases to occur from exposure to fecally contaminated food. Food can be contaminated before retail distribution, such as lettuce or fruits contaminated at the growing or processing stage; therefore, many uncooked foods have been implicated as the source of outbreaks. Cooked foods also can transmit HAV if the heat level used in preparation is inadequate to kill the virus or if food is contaminated after cooking by infected food handlers. Depending on conditions, HAV can be stable in the environment for months. ^, HAV also is stable when frozen. ^, Heating foods at temperatures >185°F (>85°C) for 1 minute or disinfecting surfaces with a 1:100 dilution of sodium hypochlorite (i.e., household bleach) in tap water inactivates HAV.

Foodborne hepatitis A infection outbreaks continue to be reported globally, some of which can be large or spread over a wide geographic area. ^{, , ,} Outbreaks of hepatitis A following ingestion of shellfish have become increasingly uncommon in high-income countries, but outbreaks related to shellfish living in sewage-polluted waters are still occasionally identified. Recently implicated shellfish have included raw scallops and mussels.

Several recent large outbreaks traced to contamination of produce prior to distribution have been reported from the United States, Europe, Australia, and New Zealand. Recently implicated produce products have included frozen pomegranate arils, ^{, ,} frozen berries, ^, fresh blackberries, and semidried tomatoes. Of note, a large multi-country outbreak in Europe in 2013–2014 was associated with frozen mixed berries and mixed berry cakes/pastries. A systematic review of global hepatitis A outbreaks associated with frozen fruits identified 12 outbreaks involving 2114 cases from 2008–2018.

Hepatitis A infection clusters due to infected food handlers continue to be an issue, with recent reports in Germany ^, and Spain. One of the clusters in Germany was due to spillover of an MSM-associated genotype.

Foodborne outbreaks can be resource intensive to investigate and control, and it may be challenging to identify the point source or source country of the contaminated produce. ^, However, molecular methods now allow for increased identification of common-source foodborne hepatitis A outbreaks.

Waterborne

Waterborne outbreaks of hepatitis A infection are uncommon and are generally related to contamination with sewage or inadequate treatment of water. Waterborne outbreaks are also often difficult to differentiate from other forms of transmission in the absence of well-designed studies. However, outbreaks associated with contaminated water supplies have been reported in countries with poor water sanitation and infrastructure, such as India and Thailand.

Vertical

The prevalence of hepatitis A infection during pregnancy is low and vertical transmission of HAV is rare. Rare published case reports describe intrauterine transmission of HAV during the first trimester, resulting in fetal meconium peritonitis. ^, The risk of transmission from pregnant persons in whom hepatitis A develops in the third trimester of pregnancy to newborns seems to be low. ^, However, newborns who acquire infection in this manner are usually asymptomatic. An outbreak among hospital staff related to exposure to an infected asymptomatic infant has been reported.