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Inactivated Hepatitis A Vaccine (HM175 Strain)

A Preliminary Review of its Immunogenicity, Protective Potential and Tolerability in At-Risk Patients

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Summary

Synopsis

Hepatitis A is endemic in many developing countries, with asymptomatic infection conferring lifelong immunity to most indigenous children. However, as sanitation improves worldwide, the acquisition of natural immunity at an early age decreases. As a consequence, the incidence of symptomatic hepatitis A infection is increasing in many areas. Formaldehyde-inactivated hepatitis A vaccine [HM175 strain; available in 360, 720 or 1440 enzyme-linked immunosorbent assay (ELISA) unit (EU) doses] has been shown to be immunogenic in adults and children, with antibodies persisting for at least 5 years and potentially several decades.

A large randomised double-blind trial in Thai children has shown the protective efficacy of the vaccine to be 95%. Pharmacoeconomic analyses have demonstrated greater cost effectiveness or better cost-benefit ratios for the vaccine than are seen with passive immunisation for travellers or army personnel making multiple trips to endemic areas.

The vaccine is well tolerated, with the most common adverse effect being mild local pain.

Thus, hepatitis A vaccine (HM175 strain), which appears to be cost effective in selected populations including travellers and military personnel, is an effective and well tolerated vaccine offering long term prevention of hepatitis A viral infection.

Overview of Hepatitis A Virus Infection

The hepatitis A virus, a member of the Picornavirus family, is extremely resistant to environmental conditions. In developing countries, endemic hepatitis A results in asymptomatic infection and subsequent lifelong immunity in most children before the age of 5 years. However, the prevalence of previously infected, immune individuals is declining in many developed and developing countries as a result of better hygiene conditions and improvements in the standard of living. As the endemicity of hepatitis A virus decreases, the average age of exposure and subsequent infection has shifted to older age groups. Since expression of clinical disease is highly age-related, this shift of infection to older age groups increases the number of clinical infections, and the risk of fulminant hepatitis and possibly death increases.

Immunogenicity of Hepatitis A Vaccine (HM175 Strain)

The formaldehyde-inactivated hepatitis A vaccine, developed from the HM175 strain and adapted to MRC-5 human diploid cells, is immunogenic in adults and children.

In adult volunteers receiving the dosage schedule of 720 enzyme-linked immunosorbent assay (ELISA) units (EU) at months 0,1 and 6, seroconversion rates ranged from 88 to 100% [geometric mean titres (GMT) of antibody to hepatitis A (anti-HAV) 158 to 529IU/L] after the first dose, 98 to 100% (GMTs 478 to 832 IU/L) after the second and 100% (GMTs 2520 to 6729 IU/L) after the booster. Administration of 1440EU at 0 and 6 or 12 months resulted in 100% seroconversion 1 month after the second dose, with GMTs of 2320 to 4775 IU/L.

Similar results were achieved in children administered hepatitis A 360EU in a 3-dose schedule. GMTs were lower in adults >40 years of age than in those aged <40 years, but seroconversion rates were similar in both groups after the second dose. Women appear to have a stronger immunological response to hepatitis A vaccine than men. The immunological response in patients with human immunodeficiency virus infection or chronic hepatitis B infection was lower than that seen in healthy volunteers.

Clinical studies have demonstrated persistence of antibodies for at least 5 years after the initial dose, and estimations based on the rate of decrease in anti-HAV antibody titres predict continued persistence for at least 20 years.

Concomitant administration of immunoglobulin or hepatitis B vaccine with hepatitis A vaccine in volunteers resulted in similar rates of seroconversion but lowered anti-HAV GMT levels versus hepatitis A vaccine alone. Seroconversion rates after completion of the immunisation schedule were similar when the hepatitis A vaccine under review was compared with hepatitis A virus strain GBM or strain RG-SB.

Attenuation of disease and reduced viral shedding in the faeces was noted when hepatitis A vaccine 360 or 720EU was administered to laboratory animals after exposure to the virus. Complete protection against disease was offered by postexposure administration of 1440EU to marmosets.

Protective Efficacy

The definitive randomised double-blind trial investigating the protective efficacy of hepatitis A vaccine (HM175 strain) involved over 38 000 children in Thailand. The control group received hepatitis B vaccine, and the resulting protective efficacy for hepatitis A vaccine was 95% for the whole vaccination course of 360EU at 0, 1 and 12 months. Other smaller-scale or less well controlled trials have also indicated efficacy of the vaccine in various at-risk populations.

Pharmacoeconomic Considerations

Pharmacoeconomic analyses of hepatitis A prevention for travellers from industrialised countries journeying to countries with moderate to high endemicity have shown that hepatitis A vaccine is more cost effective or has a better cost-benefit ratio than passive immunisation for individuals making multiple (≥3) trips over a period of ≤10 years. Most analyses used a decision-tree-based model and a hypothetical cohort. The use of a 2-dose regimen of hepatitis A vaccine 1440EU modestly improved the cost-effectiveness ratio compared with a 3-dose regimen (720EU). Active immunisation was estimated to prevent far more cases of hepatitis A infection than passive immunisation, although neither strategy was deemed to be cost saving compared with non-intervention in travellers. However, over a 10-year period, significant cost savings would be achieved with active (but not passive) immunisation of French service volunteers stationed in developing countries, since this group has a relatively high risk of exposure and low initial seroprevalence. In general, hepatitis A vaccine was estimated to have a better cost-benefit ratio than immunoglobulin among UK or United Nations military personnel who are likely to be deployed to developing countries more than once.

Tolerability

Hepatitis A vaccine is well tolerated. The most frequent adverse reaction (occurring with about 35% of doses) is mild pain at the injection site. General symptoms associated with the vaccine include fatigue, headache and malaise (<10% of doses). Generalised rash occurs rarely. Neurological reactions (such as transverse myelitis, Guillain-Barré syndrome, encephalopathy or neuralgic amyotrophy) also occur rarely but a causative association with the vaccine has not been proven. Available evidence suggests that the 1440EU dose is as well tolerated as the 720EU dose.

Dosage and Administration

Hepatitis A vaccine should be administered by intramuscular injection into the deltoid region. In the US, adults receive 2 doses of 1440EU at months 0 and 6 to 12, and children and adolescents (aged 2 to 18 years) receive 360EU at months 0, 1 and 6 to 12 or 720EU at months 0 and 6 to 12. In Canada and some countries in Europe, adults may receive 720EU at months 0, 1 and 6 to 12 or 1440EU at months 0 and 6 to 12. Similarly, in some European countries, children may receive 360EU at months 0, 1 and 6 to 12.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Antona J. Wagstaff, Greg L. Plosker & Julia Balfour

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  1. Antona J. Wagstaff
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  2. Greg L. Plosker
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  3. Julia Balfour
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Various sections of the manuscript reviewed by: B.R. Holzer, Department of Medicine, University of Berne, Berne, Switzerland; B.J. McMahon, Department of Medicine, Alaska Native Medical Center, Anchorage, Alaska, USA; J.T. Stapleton, Division of Infectious Diseases, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA; G. Tormans, Department of Epidemiology and Community Medicine, University of Antwerp, Antwerp, Belgium; P. Van Damme, Centre for the Evaluation of Vaccination, Epidemiology and Community Medici University of Antwerp, Antwerp, Belgium; E. Van Doorslaer, Institute for Medical Technology Assessment Erasmus University, Rotterdam, The Netherlands; G. Wiedermann, Institute for Specific Prophylaxis and Tropical Medicine, University of Vienna, Vienna, Austria; L. Yuan, Department of Preventive Medicine, University of Toronto, Toronto, Ontario, Canada.

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Wagstaff, A.J., Plosker, G.L. & Balfour, J. Inactivated Hepatitis A Vaccine (HM175 Strain). Clin. Immunother. 6, 68–88 (1996). https://doi.org/10.1007/BF03259353

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