Randomized comparative trial of interferon- versus placebo in hepatitis B vaccine non-responders and hyporesponders Paul N. Goldwater Adults who had received 4 x 20 #9 doses of hepatitis B (Engerix-B) vaccine (appropriately administered) and who had failed to develop detectable anti-HBs or who had had a minimal response ( < 10 IU 1- x) were randomized to receive either a fifth dose of Engerix-B (20#9) plus 1 million units of interferon-~ or a fifth dose of vaccine plus saline placebo intramuscularly (deltoid). Both vaccine and test material were given together in one syringe and participants were blind as to the syringe contents. Anti-HBs was tested (by enzyme immunoassay) one to three months following the injection. Anti-HBs results from the 150 non-responders (NR) and the 26 hyporesponders (HR) are reported. Of NRs receiving a fifth dose plus placebo, 41% developed anti-HBs, whilst 53% of those receiving interferon-~ developed anti-HBs. The response rates did not differ significantly. Of HRs receiving vaccine plus placebo, 70% showed an increase in their anti-HBs titre, while 87.5% of those receiving interferon-~ with vaccine had titre rises. Vaccinee groups were well matched for age, sex and body mass index and the interval between injection and venepuncture. Side-effects from interferon-c~ were of short duration and were tolerated by vaccinees seeking protection from hepatitis B infection. On the basis of this study, a fifth dose of vaccine in non- and hyporesponsive vaccinees is recommended. Interferon-c~ was of unproven value but it may increase the likelihood of seroconversion in NRs and its use could be considered in subjects at continued high risk of contracting hepatitis B. Anti-HBs responses were measurably higher in interferon-o~ recipients than in placebo recipients. Keywords: Hepatitis B vaccine; non-response; interferon In every population of vaccinees, a small proportion fail to mount a measurable response or do not develop protective levels of antibody. In the case of healthy hepatitis B (HB) vaccine recipients, the response rate seems to decline with increasing age 1 3, and other factors such as obesity 2 5, smoking2,3,6,7 and genetic make- up5,8 1o also play a role. Immunocompromised individ- uals such as haemodialysis patients and renal and other transplant patients have much higher rates of non- responsiveness and hyporesponsiveness ~1. At the lower end of the bimodal response to hepatitis B vaccine are individuals who are more likely to be homozygous for two extended haplotypes: [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7] 1°. This finding indicates that a poor response to hepatitis B vaccine is inherited as a recessive trait requiring non-response genes for HBsAg on both MHC haplotypes. Heterozygous individuals have higher antibody responses than their homozygous counterparts. Another possible factor in hyporesponsive- Microbiology Department, The Adelaide Children's Hospital (Women's and Children's Hospital), North Adelaide, South Australia 5006. (Received 2 October 1992; revised 5 January 1993; accepted 23 February 1993) 0264-410X/94/05/0410-05 © 1994 Butterworth-Heinemann Ltd 410 Vaccine 1994 Volume 12 Number 5 ness to HB vaccine is the role played by suppressor lymphocytes 12. Cytokines such as interferons and interleukin-2 affect various aspects of the immune response and have been used successfully to augment the immune response to vaccine antigens including killed rabies virus 13, Plasmodium falciparum malaria vaccine 14 and HBsAg 15-17. However, almost no data exist regarding the effect of interferon on healthy adult hepatitis B vaccine non-responders. Grob et al.15 refer to only two 'low responders' in their study. With this in mind, a randomized trial of interferon-~ versus placebo given with a fifth dose of HB vaccine was conducted in HB vaccine non-responders and hypo- responders to determine the existence or otherwise of an immunostimulatory effect of interferon. A further objective was to ascertain the effect of a fifth dose of HB vaccine (plus placebo) on anti-HBs response. The possible side-effects of interferon-~ were studied also. METHODS Healthy adult volunteers were recruited from the South Australian Police Department (of which the vaccinated workforce totalled 3500, all of whom had received at least