Efficient postexposure prophylaxis by hepatitis A vaccine

Authors

  • Samira Fafi-Kremer,

    1. Institut National de la Santé et de la Recherche Médicale,Unit 748 Strasbourg, France
    2. Université Louis Pasteur Strasbourg, France
    3. Institut de Virologie, Hôpitaux Universitaires de Strasbourg Strasbourg, France
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  • Françoise Stoll-Keller,

    1. Institut National de la Santé et de la Recherche Médicale,Unit 748 Strasbourg, France
    2. Université Louis Pasteur Strasbourg, France
    3. Institut de Virologie, Hôpitaux Universitaires de Strasbourg Strasbourg, France
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  • Thomas F. Baumert

    1. Institut National de la Santé et de la Recherche Médicale,Unit 748 Strasbourg, France
    2. Université Louis Pasteur Strasbourg, France
    3. Service d'Hépatogastroentérologie, Hôpitaux Universitaires de Strasbourg Strasbourg, France
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  • Potential conflict of interest: Nothing to report.

Victor JC, Monto AS, Surdina TY, Suleimenova SZ, Vaughan G, Nainan OV, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007;357:1685-1694. (Reprinted with permission.)

Abstract

BACKGROUND: Hepatitis A vaccine administered to persons after exposure to the hepatitis A virus has not been compared directly with immune globulin, which is known to be highly effective in preventing hepatitis A when given within 2 weeks after exposure to the virus. METHODS: We randomly assigned household and day-care contacts, 2 to 40 years of age, in Almaty, Kazakhstan, to receive one standard age-appropriate dose of hepatitis A vaccine or immune globulin within 14 days after exposure to patients with hepatitis A. Instances of laboratory-confirmed, symptomatic hepatitis A infection occurring between 15 and 56 days after exposure were then assessed during active follow-up of all susceptible contacts. RESULTS: Of 4524 contacts who underwent randomization, 1414 (31%) were susceptible to hepatitis A virus and 1090 were eligible for the per-protocol analysis. Among these contacts, 568 received hepatitis A vaccine and 522 received immune globulin. Most contacts were children (average age, 12 years), and most received prophylaxis during the second week after exposure (average interval after exposure, 10 days). The baseline characteristics of the contacts were similar in the two groups. Symptomatic infection with hepatitis A virus was confirmed in 25 contacts receiving vaccine (4.4%) and in 17 contacts receiving immune globulin (3.3%) (relative risk, 1.35; 95% confidence interval, 0.70 to 2.67). CONCLUSIONS: Low rates of hepatitis A in both groups indicate that hepatitis A vaccine and immune globulin provided good protection after exposure. Although the study's prespecified criterion for noninferiority was met, the slightly higher rates of hepatitis A among vaccine recipients may indicate a true modest difference in efficacy and might be clinically meaningful in some settings. Vaccine has other advantages, including long-term protection, and it may be a reasonable alternative to immune globulin for postexposure prophylaxis in many situations

Comment

Hepatitis A virus (HAV), the causative agent of type A viral hepatitis, is transmitted by the fecal-oral route. Virus transmissibility is of greatest concern during the incubation phase (15 to 50 days) where the patients remain asymptomatic despite high titers of virus within liver tissue, bile, stool, and to a lesser extent, blood. Hepatitis A is often asymptomatic when young children are infected. If infection is delayed until adolescent or adult age, it frequently results in symptomatic self-limited hepatitis with symptoms ranging from mild and transient to severe, prolonged, and cholestatic hepatitis. With the improvement in sanitation and the introduction of highly effective HAV vaccines, the incidence of HAV declined dramatically in countries with a high health-care standard. However, sporadic cases and outbreaks continue to occur caused even by the growing population mobility (such as travellers and immigrants) from developing to industrialized countries or by virus spread through contaminated food coming from highly endemic countries.1 Moreover, with the decrease in the incidence of HAV infection, a progressive increase in susceptible individuals is noted and the age distribution of the disease has shifted from children to adults, who are more likely to have severe manifestations of hepatitis A. For decades, the Advisory Committee on Immunization Practices (ACIP) of the United States recommended immune globulin for prophylaxis after exposure to HAV.

Immune globulin seems to have 90% efficacy for postexposure prophylaxis and attenuates symptoms of hepatitis A. Many reports have suggested that similar antibody levels can be achieved following immunization with inactivated vaccine.1, 2 Because immune globulin is a blood product unavailable in several countries, provides only short-term protection, and because declining concentrations of antibodies to HAV have been reported for some globulin preparations,1 many experts have proposed the use of the vaccine as a postexposure strategy. Sagliocca et al. had shown that a single dose of hepatitis A vaccine provided 79% effective protection against HAV infection when given to household contacts of subjects with HAV infection.3 These data were in agreement with previous postexposure prophylaxis data from outbreak control and immunization studies in animals.4, 5 Nevertheless, the ACIP still recommended the use of immune globulin because large clinical trials comparing the efficacy of the HAV vaccine with that of immune globulin were lacking.

Following the randomized, double-blind, active-controlled noninferiority trial from Victor et al.,6 this recommendation finally changed. Victor et al. compared the efficacy of the hepatitis A vaccine and the immune globulin, as a postexposure prophylaxis, in 1,090 persons aged 2 to 40 years susceptible to hepatitis A and who were exposed to an index patient with confirmed hepatitis A.6 Most of the contacts were children with an average age of 12 years. The study was performed in Almaty in Kazakhstan, where hepatitis A is of intermediate endemicity. Symptomatic hepatitis A in index and contact persons was confirmed on the basis of clinical symptoms, presence of IgM antibodies directed against HAV in blood, and a serum alanine aminotransferase level at least twice the upper limit of the normal range. The vaccine or immune globulin were administered at ≤ 14 days after exposure to HAV, and the primary study end point was laboratory-confirmed symptomatic hepatitis A occurring between 15 and 56 days after exposure. Symptomatic hepatitis A was observed in 25 of 568 (4.4%) recipients of hepatitis A vaccine and 17 of 522 (3.3%) immune globulin recipients (relative risk: 1.35; 95% confidence interval: 0.70 to 2.67). The low rates of hepatitis A in both groups indicated that hepatitis A vaccine and immune globulin provided good protection after exposure.6

In this well-designed, large randomized clinical trial, the investigators clearly demonstrate that active immunization by HAV vaccine against HAV infection is effective for postexposure prophylaxis and approaches that of immune globulin in healthy children and adults aged < 40 years.6 This finding is important because the HAV vaccine provides numerous advantages, including high safety and immunogencity, long-term protection, high availability, ease of administration, and costs.

What are the limitations of the study? First, the subjects in the study of Victor et al. were limited to persons with 2 to 40 years of age with no history of HAV infection. Patients with chronic liver disease had been excluded.6 These inclusion criteria may limit the conclusions for older patients or patients with chronic liver disease. Second, although the study's prespecified criterion for noninferiority was met, the slightly higher rates of hepatitis A among vaccine recipients may indicate a true modest difference in efficacy. This difference could be clinically meaningful for persons who are likely to have severe illness if infected with HAV, such as older persons, those with chronic liver disease, or immunocompromised patients.6

How can the similar efficacy of the vaccine compared with immune globulin for postexposure prophylaxis be explained? Administration of immune globulin provides immediately highly effective but relatively short-term (3 months) protection against clinical hepatitis A. This protection is exclusively due to the presence of circulating, passively transferred neutralizing antibodies to HAV.7 In contrast, the HAV vaccine is based on viral particles that are produced in cell culture, purified, inactivated with formalin, and adsorbed to an aluminium hydroxide adjuvant. Immunization induces antibody levels similar to those obtained after passive immunization with immune globulin within 2 weeks after vaccination.1 In addition, the HAV vaccine induces a readily detectable T cell response.2 Moreover, this early proliferative T cell response is accompanied by a marked interferon-gamma production contributing to the clearance of the virus in infected hepatocytes.2 Thus, in actively vaccinated individuals both a rapid induction of neutralizing antibodies and as well as early priming of cellular immune responses contribute toward prevention of symptomatic acute hepatitis (Fig. 1).

Figure 1.

Humoral and cellular immune response induced by HAV vaccine. The HAV vaccine is based on viral particles that are produced in cell culture, purified, inactivated with formalin, and adsorbed to an aluminium hydroxide adjuvant. Immunization induces HAV-neutralizing antibodies within 2 weeks after vaccination in almost all vaccinees. In addition, the HAV vaccine induces a readily detectable T cell response. This early proliferative T cell response is accompanied by a marked interferon-gamma production contributing to viral clearance of infected hepatocytes.

On the basis of the results of the trial from Victor and colleagues, the ACIP changed its recommendations regarding postexposure prophylaxis against HAV infection in October 2007.8 Single-antigen HAV vaccine is now recommended instead of immune globulin for immunocompetent subjects without chronic liver disease aged between 2 and 40 years old.8 For infants aged <12 months, immunocompromised persons, persons with chronic liver disease, or persons with contraindications, immune globulin should be used.8

Finally, this study also provides real progress for travelers and particularly last-minute travelers. Until now, the Centers of Disease Control and Prevention (CDC) and the World Health Organization stated that travelers should be vaccinated 4 weeks before departure, and the CDC recommended the use of vaccine in combination with immune globulin if the departure date is earlier than 4 weeks. Following the new recommendations, most healthy persons traveling to or working in countries with high or intermediate endemicity could be vaccinated at any time before departure.8

Acknowledgements

The authors thank Jack T. Stapleton (University of Iowa) for helpful discussions.

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