Comprehensive tracking of Hepatitis A vaccines including inactivated formulations, travel immunization, outbreak control, and elimination strategies. Hepatitis A vaccine (licensed 1995) transformed a common childhood disease into a preventable infection through routine vaccination.
Global Burden: WHO estimates 1.5 million clinical cases annually worldwide (2016), with 7,900 deaths (2019, mostly in low-income countries with poor sanitation). True burden likely 10x higher due to subclinical infections. Pre-vaccine era U.S. (1990s): 30,000-35,000 reported cases annually (true incidence ~150,000-200,000 accounting for underreporting and asymptomatic cases), leading cause of acute viral hepatitis. Post-universal vaccination (2006 onwards): 90-95% reduction with 1,500-3,500 annual reported cases by 2020s. Developed countries saw similar declines post-vaccination (Israel, Europe, Australia). Geographic distribution: High endemicity (≥8% HAV seroprevalence by age 10): Sub-Saharan Africa, South Asia, parts of Southeast Asia - most children infected by age 10 asymptomatically. Intermediate endemicity (2-7% by age 10): Middle East, Latin America, parts of Eastern Europe - mixed childhood/adult infection patterns. Low endemicity (<2% by age 10): North America, Western Europe, Japan, Australia - paradox creates susceptible adult population vulnerable to severe disease when exposed.
Clinical Manifestations - Age-Dependent Severity: HAV causes acute self-limited hepatitis (no chronic infection unlike HBV/HCV). Incubation: 15-50 days (average 28 days). Children <6 years: 70-80% asymptomatic or mild non-specific illness (fever, malaise, no jaundice - "anicteric hepatitis"), important epidemiologic source transmitting to adults asymptomatically. Older children/adults: Symptomatic disease common (70-80% develop jaundice), prodrome (abrupt onset fatigue, nausea, vomiting, anorexia, right upper quadrant pain, fever), icteric phase (jaundice develops day 5-7, dark urine, pale stools, pruritus from bile salt deposition), hepatomegaly and liver tenderness, symptoms last 2-8 weeks (prolonged in some cases - months), full recovery expected in 99%+ cases. Severity increases with age: Adults >50 years have higher hospitalization rates (20-40% vs. 10% in younger adults), case fatality 0.3-0.6% in adults vs. <0.1% in children. Complications rare but serious: Fulminant hepatic failure (0.1-0.5% of icteric cases, higher in adults >50 and those with underlying liver disease, requires liver transplant evaluation), cholestatic hepatitis (prolonged jaundice 3-6 months from cholestasis, eventual complete recovery), relapsing hepatitis (10-15% have symptom recurrence weeks-months after apparent recovery, virus reappears in stool, ultimately resolves). No chronic infection or carrier state (virus cleared completely after acute infection, lifelong immunity follows).
Viral Biology: Hepatitis A virus (HAV) is picornavirus, single-stranded RNA, non-enveloped virus remarkably stable in environment (survives weeks at room temperature, resistant to freezing, acid, some disinfectants, heat-inactivated at 85°C for 1 minute). Transmission: Fecal-oral route via person-to-person contact (direct contact with infected person, diaper changing, sexual contact - especially among men who have sex with men), contaminated food/water (shellfish from contaminated waters classic source, fresh produce irrigated with contaminated water, food handlers with HAV shedding virus), international travel to endemic areas (most common risk factor in U.S. cases - travelers to Latin America, Asia, Africa). No airborne or blood transmission (contrast to bloodborne HBV/HCV). Contagious period: Peak infectivity 1-2 weeks before symptom onset (when virus shedding highest in stool - patients unknowingly transmit), declines after jaundice onset, can shed virus 2-3 weeks into illness. Incubation period creates delayed recognition of outbreaks (2-4 week lag between exposure and symptoms complicates source identification).
Travel Health Supplies →Technology: Inactivated whole virus vaccine. HAV grown in cell culture (MRC-5 human diploid cells), inactivated with formaldehyde, purified and adsorbed to aluminum hydroxide adjuvant. Two formulations: Pediatric (720 ELISA units/0.5 mL) for ages 12 months-18 years, Adult (1440 ELISA units/1.0 mL) for ≥19 years.
Schedule: Two-dose series: Dose 1 at initial visit, Dose 2 at 6-12 months (minimum 6 months, optimal 6-12 months, can extend to 18 months if necessary). Intramuscular injection (deltoid in adults/children, anterolateral thigh in infants). U.S. routine childhood vaccination: Dose 1 at 12-23 months, Dose 2 at ≥6 months later (typically by 2-3 years old). Adults at risk: Two-dose series regardless of age.
Efficacy: After dose 1: 95-100% develop protective antibodies by 2-4 weeks (provides protection for travel departing ≥2 weeks post-dose 1). After dose 2: >99% seroprotection achieved. Duration: Antibody titers decline slowly over years but protection persists - studies show antibodies detectable 20+ years post-vaccination, mathematical modeling predicts lifelong immunity (immunological memory established, anamnestic response if re-exposed even if antibodies decline). Real-world effectiveness: Clinical trials and post-licensure surveillance show 94-100% prevention of symptomatic HAV infection.
Safety: Excellent safety profile, one of the safest vaccines. Common reactions: Injection site pain (50-55%), headache, fatigue (10-15%), low-grade fever (<5%). Serious adverse events extremely rare, no causal association with any serious condition in extensive post-marketing surveillance (>100 million doses administered globally). Safe in: Pregnancy (limited data but inactivated vaccine, theoretical low risk), HIV-positive individuals (reduced response but still protective in many), chronic liver disease patients (especially important to vaccinate as HAV causes severe disease in these patients).
Usage: Most widely distributed HAV vaccine globally, WHO-prequalified, available in >100 countries. Accounts for 60-70% of global HAV vaccine doses.
Technology: Similar inactivated HAV vaccine using different cell line (MRC-5 cells) and formulation. Inactivated with formaldehyde, aluminum hydroxyphosphate sulfate adjuvant. Two formulations: Pediatric/Adolescent (25 units/0.5 mL) for 12 months-18 years, Adult (50 units/1 mL) for ≥19 years.
Schedule: Identical to Havrix - two-dose series with dose 2 at 6-18 months after dose 1. Interchangeable with Havrix (can complete series with either vaccine regardless of which given first, though using same product preferred).
Efficacy & Safety: Equivalent to Havrix (>95% seroprotection after dose 1, 99%+ after dose 2, 20+ year duration). Safety profile indistinguishable from Havrix. Non-inferior in head-to-head trials.
Usage: Widely used in U.S. (30-40% of U.S. HAV vaccine market), less prevalent internationally than Havrix but available in many countries.
Composition: Combined inactivated HAV (720 ELISA units - same as pediatric Havrix) plus recombinant HBsAg (20 μg - same as adult Engerix-B). Single injection providing immunity to both hepatitis A and B. Adult formulation only (≥18 years).
Schedules: Standard 3-dose series: 0, 1, 6 months (dose 1 at initial visit, dose 2 at 1 month, dose 3 at 6 months). Accelerated 4-dose series: 0, 7, 21-30 days, 12 months (for travelers departing soon needing rapid protection to both HAV and HBV, first 3 doses provide short-term immunity, 4th dose at 12 months ensures long-term protection). Intramuscular deltoid injection.
Efficacy: Non-inferior to giving Havrix and Engerix-B separately for both antigens. After 3-dose series: >95% protected against HAV, >95% protected against HBV. Duration: 20+ years both HAV and HBV.
Advantages: Fewer total injections (3 vs. 4-5 if giving separate HAV 2-dose + HBV 3-dose series), simplified schedule for travel medicine (common to need both for international travel), improved compliance (combined reduces clinic visits), cost-effective. Disadvantages: Adult only (no pediatric formulation - children receive separate HAV and HBV vaccines), fixed dosing (cannot adjust HAV vs. HBV components independently, problematic if someone needs boosters of only one component).
Usage: Popular in travel medicine clinics (traveler getting both vaccines simultaneously very common), occupational medicine (healthcare workers, first responders needing HAV and HBV), also used for MSM and other high-risk groups needing both vaccines. Accounts for 15-20% of HAV vaccine doses in U.S. (primarily adults).
U.S. Universal Childhood Vaccination (2006): ACIP expanded from targeted high-risk groups to all children: First dose at 12-23 months (integrated into routine childhood schedule), second dose ≥6 months later. Rationale: Pre-2006 targeted approach failed to control disease (vaccination of high-risk groups only reduced cases 30-40%, most cases had no identified risk factors), children primary reservoir (asymptomatic/mild infections in children spread to adults), universal childhood vaccination most cost-effective strategy for elimination. Impact: U.S. HAV incidence declined 95% (from ~31,000 annual cases pre-2006 to ~1,500-3,500 by 2015-2020), herd immunity protected unvaccinated adults (children no longer spreading virus reducing transmission to adults), near-elimination in states with highest baseline burden (Arizona, California saw >97% declines). Similar success in other countries implementing universal childhood vaccination (Israel, Argentina, parts of Europe).
Adult Risk Groups (Pre-Exposure Prophylaxis): International travelers to endemic regions (single most common indication in adults - all travelers to Latin America, Africa, Asia except Japan/Singapore/Hong Kong), men who have sex with men (MSM - increased HAV transmission in this population, multiple U.S. outbreaks), people who use drugs (injection and non-injection - associated with increased HAV risk), people with chronic liver disease (HAV causes severe/fulminant disease on background cirrhosis, any cause chronic liver disease indication for HAV vaccine - HCV, alcoholic liver disease, NASH, etc.), people experiencing homelessness (crowding, sanitation challenges increase HAV risk, multiple outbreak clusters), clotting factor disorder recipients (contaminated blood products historically transmitted HAV), laboratory workers handling HAV, childcare workers during outbreaks. ACIP recommends vaccination any adult requesting protection or with risk factors.
Post-Exposure Prophylaxis (PEP): HAV vaccine highly effective as PEP if given within 2 weeks of exposure: Healthy individuals 12 months-40 years: HAV vaccine alone within 2 weeks of exposure (85-90% effective preventing disease). Immunocompromised, chronic liver disease, adults >40 years: HAV vaccine PLUS immune globulin (IG, 0.1 mL/kg IM) within 2 weeks for optimal protection (vaccine provides active long-term immunity, IG provides immediate passive immunity). Infants <12 months: IG alone (vaccine not licensed <12 months). Exposures warranting PEP: Household/sexual contact of HAV case, childcare center exposure (staff and attendees), common-source exposure (restaurant outbreak - IG to patrons if infected food handler identified within 2 weeks of last food service). IG shortage 2017-2020 led to vaccine-only PEP strategy expanded to all ages (vaccine alone proven effective even >40 years in outbreak settings when IG unavailable).
CDC Hepatitis A: Vaccination recommendations, outbreak information, travel advisories. CDC Hep A
WHO - Hepatitis A: Global disease burden, vaccination strategies, position papers. WHO Hep A
CDC Pink Book - Hepatitis A Chapter: Comprehensive epidemiology, clinical features, vaccination guidance. Pink Book
ACIP Hepatitis A Vaccine Recommendations: Detailed schedules, risk groups, post-exposure prophylaxis. ACIP Recs
CDC Yellow Book - Hepatitis A: Travel-related HAV prevention, geographic risk assessment. Yellow Book
Travel Health Notices: Current HAV outbreak alerts for travelers. Travel Notices