Clinical assessment of the safety and efficacy of an inactivated hepatitis A vaccine: rationale and summary of findings

Abstract

The objectives for the clinical testing of the inactivated hepatitis A vaccine developed by SmithKline Beecham Biologicals are reviewed and the results obtained are summarized. The first studies were carried out in healthy young adult volunteers using pilot vaccine lots prepared from the CLF and HM175 strains of hepatitis A virus (HAV). It was established that the candidate vaccines were well-tolerated, caused no hypersensitivity reactions and elicited a strong antibody response. As the yield in production with the HM175 strain was higher it was preferred over the CLF strain for further development of a vaccine. A dose-range study with HM175 vaccine in adults showed that an antigen dose of 720 ELISA units (ELU) produced almost 100% seroconversion after one injection. This dose was therefore chosen as appropriate for adults. A dose of 360 ELU was used in children. To date, a total of 67 studies in 18 countries involving 47 145 subjects, including 20 586 control subjects, have been initiated. In these studies, 55 259 doses of HM175-derived hepatitis A vaccine have so far been administered. This extensive experience has shown that the vaccine is well-tolerated, causing essentially only mild, transient local reactions. Vaccine reactogenicity was assessed using symptom checklists, filled in by the volunteers or their parents, for a period of 4 days following vaccination. Blood samples were obtained at different times after vaccination to evaluate the immune response. Clinical studies with six different lots, manufactured using commercial-scale production methods, have been carried out on 2901 adults. These studies have shown that a seroconversion rate of 95.7% (1225/1280) is obtained one month after the first vaccine dose. A second dose, given after one month, resulted in seroconversion of 99.8% (1278/1281) of the subjects. Geometric mean anti-HAV concentrations (GMC) at these times were 304 and 517 mIU/ml, respectively. These and other studies have shown that two vaccine doses administered one month or 2 weeks apart give antibody titres which are ≈ 25-times higher than those observed following the administration of immune serum globulin (Ig), which is known to protect against disease. In addition, adequate levels of antibodies persisted for up to one year after two doses of vaccine. Booster doses of vaccine at either 6 or 12 months following the start of the primary vaccination course induced GMCs of 4114 and 9051 mIU/ml, respectively. Vaccine-induced antibodies have been shown to have virus-neutralizing activity. Challenge studies in chimpanzees demonstrated that the vaccine can protect them against infection. Antibodies induced in humans by vaccine will passively protect chimpanzees against disease, but not infection, in the same way as Ig. A large-scale field trial in primary school age children provided direct evidence of a high level of protection against disease in humans for one year. Studies have also shown that the vaccine can be simultaneously administered, at another site, with Ig or hepatitis B vaccine. This inactivated hepatitis A vaccine has been shown to be very well tolerated clinically and to be highly immunogenic, eliciting levels of specific antibodies which protect against hepatitis A.