Hepatitis vaccines

Plasma-derived hepatitis B virus vaccine

Plasma-derived hepatitis B virus vaccine is prepared from the plasma of chronic HBsAg carriers, and consists of purified, inactivated 20-nm HBsAg particles adsorbed on to an aluminium adjuvant. The use of a vaccine produced with plasma derived from infected individuals represented a major departure from conventional approaches, and safety testing has therefore been designed to cover all possibilities of risk and to ensure freedom from transmission of residual HBV and other blood-borne agents. Various clinical trials [ , ] have confirmed the safety of plasma-derived hepatitis B virus vaccines produced by different manufacturers. Fears that plasma-derived vaccine may transmit AIDS can be considered unfounded.

Subsequent to the identification of HIV and the growing knowledge of its relatively easy inactivation with procedures such as heat or triple-step chemical inactivation, the complete safety and suitability of plasma-derived vaccines that meet WHO requirements has now been generally accepted and their safety demonstrated [ ]. This type of hepatitis B vaccine is generally well tolerated. The most common adverse reaction has been local soreness at the injection site. Less common local reactions include erythema, swelling, and induration; all usually subside within 48 hours. Transient low-grade fever has occurred occasionally; but malaise, fatigue, vomiting, dizziness, myalgia, and arthralgia have been infrequent. Individual reports of more severe suspected adverse reactions (erythema multiforme, hepatitis-like changes in liver function, hypersensitivity, lichen planus, menstrual abnormality, myasthenia gravis, neurological disorders including transverse myelitis and Guillain–Barré syndrome, reactive arthritis, Takayasu’s arteritis, urticaria, uveitis) are very rare and are no more than could be expected by chance [ ]. In one reported case with neurological symptoms, a preceding viral illness was the likely cause and in the patient with hepatitis-like symptoms mentioned above, the possibility of other causes was not excluded. In a case with urticaria, patch tests revealed a hypersensitivity to thiomersal, the preservative in the vaccine.

By 1988 it was possible to summarize the adverse reactions reported after the distribution of over 1.8 million doses of plasma-derived hepatitis B vaccine ( Table 1 ) [ ]. From 1982 onwards, the Centers for Disease Control, the Food and Drug Administration, and the manufacturers, Merck Sharp & Dohme, had supported a special surveillance system to monitor spontaneous reports of reactions to plasma-derived hepatitis vaccine. During the first 3 years, about 850 000 persons were immunized. In all, 41 reports were received for one of the following neurological adverse events: convulsion (n = 5), Bell’s palsy (n = 10), Guillain–Barré syndrome (n = 9), lumbar radiculopathy (n = 5), brachial plexus neuropathy (n = 3), optic neuritis (n = 5), and transverse myelitis (n = 4). Half of these events occurred after the first vaccine dose. However, no conclusive causal association could be made between any neurological adverse event and the vaccine [ ].

Yeast-derived recombinant hepatitis B vaccine

The yeast-derived recombinant vaccines first licensed in 1986 represented the first vaccine of any kind manufactured by recombinant technology. The vaccines are prepared using antigen produced by recombinant technology in yeast ( Saccharomyces cerevisiae ). The recombinant vaccine produced by Merck, Sharp & Dohme was as immunogenic and protective against hepatitis B as plasma-derived vaccine [ ]. Clinical reactions in this series were mild and transient. About 17% of all recipients had pain, soreness, and tenderness at the injection site. A smaller proportion reported headache, weakness, nausea, or malaise. Between February 1984 and August 1986, 33 investigators in 19 countries carried out clinical trials with the yeast-derived recombinant hepatitis B vaccine produced by SmithKline Biologicals. Among other risk groups, neonates, patients with thalassemia and sickle cell anemia, and hemodialysis patients have been vaccinated. All the results point to the safety and acceptability of a yeast-derived vaccine. The incidence of reported reactions varied widely in different studies depending on the scrupulousness with which minor signs were reported. No serious, severe, or anaphylactic reactions occurred. The incidence of local and systemic reactions reported in each study tended to decrease after successive doses, suggesting that immunization did not induce hypersensitivity [ ].

Reports of studies of the efficacy and safety of recombinant hepatitis vaccines have been published [ ]. Table 1 shows the adverse reactions reported after the distribution of 205 000 doses of recombinant vaccine.

Third-generation hepatitis B vaccines

Between 5% and 15% of healthy immunocompetent individuals do not seroconvert after receipt of the currently licensed hepatitis B vaccines containing only the major surface protein HbsAg without pre-S epitopes. In a study of a hepatitis B vaccine containing pre-S1, pre-S2, and antigenic components of both viral subtypes adw and ayw, all three antigenic components were produced in a continuous mammalian cell line, after transfection of the cells with recombinant hepatitis B surface antigen DNA [ ]. The vaccine was manufactured as an aluminium hydroxide adjuvant formulation. The new vaccine (5, 10, 20, or 50 micrograms) was given to 68 individuals with HBs antibody titers below 10 IU/l. Seroconversion rates in the four groups were 60%, 76%, 64%, and 80%. There were local or systemic reactions in 15%. No dose-related incidence was seen.

Surveillance of hepatitis B adverse events in the USA and Australia

Adverse events after hepatitis B vaccine reported between 1 January 1991 and 31 May 1995 to the US Vaccine Adverse Events Reporting System have been reviewed [ ]. The patients included 58 neonates and 192 infants who were immunized with hepatitis B vaccine alone and 1469 infants who had received hepatitis B vaccine in combination with DTP vaccine. The serious adverse events reported in neonates and infants included fever, agitation, and apnea. The events reported for infants who received hepatitis B vaccine and DTP vaccine simultaneously were compared with the events reported for infants who received either DTP vaccine or hepatitis B vaccine alone. The reports filed for the infants who received DTP vaccine alone or in combination with hepatitis B vaccine differed from the reports filed for infants who received hepatitis B vaccine alone, suggesting that these events may have been associated with the DTP vaccine. The reviewers concluded that no unexpected adverse events had occurred in neonates and infants given hepatitis B vaccine, despite the administration of at least 12 million doses.

Between 1988 and 1996, the Australian Drug Evaluation Committee received some 600 reports of suspected adverse events after hepatitis B immunization. There were no serious events, and the overwhelming majority were well-known mild-to-moderate local or systemic reactions [ ]. Musculoskeletal symptoms, such as arthralgia, arthritis, and myalgia, were mentioned in 106 reports.

General adverse effects and adverse reactions

The reports of major adverse reactions that have been published since the introduction of recombinant hepatitis B vaccine have been reviewed [ ]. In the clinical trials with hepatitis B vaccine, the most frequent adverse reactions were soreness at the injection site, sometimes accompanied by erythema (3–29%), fatigue (15%), headache (9%), and a temperature increase higher than 37.7 °C. The postmarketing surveillance literature (4.5 million doses) showed an overall rate of one adverse reaction per 15 500 doses. Of these, local reactions were reported at a rate of 1 in 85 000 doses. Systemic reactions included nausea, rash, headache, fever, malaise, fatigue, flu-like symptoms, diarrhea, urticaria, paresthesia, and somnolence, all of which resolved, generally within 24–48 hours of vaccine administration. Reactions were less frequent with subsequent doses. Major adverse reactions have been published as case reports: anaphylaxis; urticaria, erythema nodosum, lichen planus; arthritis, Reiter’s syndrome; pulmonary and cutaneous vasculitis; systemic lupus erythematosus; glomerulonephritis; Evan’s syndrome, thrombocytopenic purpura; acute posterior multifocal placoid pigment epitheliopathy; Guillain–Barré syndrome, transverse myelitis, multiple sclerosis, acute cerebellar ataxia; chronic fatigue syndrome. Table 2 summarizes the reports. Discussing the cause of the reported major adverse reactions and a possible causal relation with vaccine administration, the authors considered that apart from anaphylaxis and urticaria, most of the reactions described were not allergic in nature and that the symptoms were those of immune-complex disease due to autoimmune mechanisms. Because of the extreme rarity of such serious adverse events, coincidence seems the simplest explanation, but an immune-complex mediated pathogenesis should not be excluded, given the close temporal relation between immunization and the onset of disease. Apart from immune-complex mechanisms, there may be reactions to other components of the vaccine, such as thiomersal, aluminium, or small quantities of yeast proteins.

Hexavalent immunization, including hepatitis B

The Hexavalent Study Group has compared the immunogenicity and safety of a new liquid hexavalent vaccine against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and Haemophilus influenzae type b (DTP + IPV + HB + Hib vaccine, manufactured by Aventis Pasteur MSD, Lyon, France) with two reference vaccines, the pentavalent DTP + IPV + Hib vaccine and the monovalent hepatitis B vaccine, administrated separately at the same visit [ ]. Infants were randomized to receive either the hexavalent vaccine (n = 423) or (administered at different local sites) the pentavalent and the HB vaccine (n = 425) at 2, 4, and 6 months of age. The hexavalent vaccine was well tolerated (for details, see the monograph Pertussis vaccines). At least one local reaction was reported in 20% of injections with hexavalent vaccine compared with 16% after the receipt of pentavalent vaccine or 3.8% after the receipt of hepatitis B vaccine. These reactions were generally mild and transient. At least one systemic reaction was reported in 46% of injections with hexavalent vaccine, whereas the respective rate for the recipients of pentavalent and HB vaccine was 42%. No vaccine-related serious adverse event occurred during the study. The hexavalent vaccine provided immune responses adequate for protection against the six diseases.