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Combined Hepatitis A and B Vaccines

A Review of Their Immunogenicity and Tolerability

  • Adis Drug Evaluation
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Summary

Abstract

Three combined hepatitis A and B vaccine preparations are commercially available in various countries: a two-dose paediatric formulation (Ambirix™) [administered at months 0 and 6–12]; and a three-dose adult (Twinrix™ Adult) or paediatric (Twinrix™ Paediatric) formulation (administered at months 0, 1 and 6).

The adult vaccine provides consistent, marked immunogenicity which is at least similar to that of its constituent vaccines used together and with a tolerability profile that is possibly improved. An accelerated, day-0, -7 and -21 regimen has also shown immunogenicity similar to that of the monovalent vaccines given concurrently, and now has an emerging role in adults likely to travel to hepatitis A virus (HAV) and/or hepatitis B virus (HBV) endemic regions within 1 month. The adult vaccine appears effective and generally well tolerated when given concurrently with monovalent typhoid vaccine (Typherix™).

Immunogenicity of the two-dose paediatric vaccine is high and appears to be similar whether administered as a month-0, -6 or month-0, -12 schedule and when compared to that of the three-dose paediatric vaccine (months 0, 1, 6), both of which provide a similar degree of protection to the adult vaccine. Although both preparations also provide high end-of-schedule seroprotection against hepatitis B surface antigen, protection between the first and second doses of the two-dose regimen appears lower than with the three-dose schedule. Therefore, the three-dose paediatric vaccine is a practical option in individuals at risk of immediate exposure to HBV, while the two-dose regimen may have an important function in immunisation programmes in regions where such risk is low.

Combined hepatitis A and B vaccines are generally well tolerated. The most frequently reported adverse events in clinical trials were injection-site pain and redness, and general fatigue and headache; most events were mild and transient. Pharmacoeconomic models suggest the combined vaccine is cost effective compared with no vaccine (in children/adolescents) or monovalent hepatitis B vaccine (in children/adolescents and prison inmates).

Conclusion: The three commercially available combined hepatitis A and B adult and paediatric vaccines are highly immunogenic and generally well tolerated; the adult vaccine demonstrates immunogenicity at least as marked as that of monovalent hepatitis A and B vaccines. While further research is required to confirm potential advantages such as improved cost effectiveness, the combined vaccines have established a key role in the prevention of hepatitis A and B in defined risk groups, and have an expanding role in population-based vaccination programmes with younger age groups.

Immunogenicity

Combined Hepatitis A and B Adult Vaccine: Seroconversion after vaccination was rapid and rates were high in randomised, nonblind comparative studies that assessed anti-hepatitis A virus (HAV) antibody seroconversion. At month 2, 96–100% of vaccinees had seroconverted, whereas 100% (geometric mean titre [GMT] 3377–5997 mIU/mL) had done so at month 7, when the anti-hepatitis B surface antigen (HBsAg) seroprotection rate was 95–98% (2099-4889 mIU/mL). Importantly, most studies reported no statistically significant differences in seroconversion and seroprotection rates between the combined vaccine and monovalent hepatitis A (Havrix™) and hepatitis B (Engerix B™) vaccines.

At month 12, an accelerated day-0, -7 and -21 schedule of the combined vaccine produced anti-HAV antibody seroconversion and anti-HBsAg seroprotection rates that were similar to those achieved with an accelerated regimen of monovalent hepatitis B vaccine plus hepatitis A vaccine (94–96% vs 92–95%), although all vaccinees had seroconverted and were seroprotected at month 13 (i.e. 1 month after booster vaccinations at month 12). Interestingly, the combined rather than monovalent vaccine schedule was associated with significantly higher (p < 0.05) GMTs of anti-HAV antibodies at all study assessment points.

Regimens comprising simultaneously administered or extemporaneously combined adult vaccine with monovalent typhoid vaccine (Typherix™) demonstrated immunogenic bioequivalence in one comparative study.

GMTs and seroconversion/seroprotection rates in several large (n ≥ 130) noncomparative trials, and a pooled analysis including some of these, closely paralleled those in comparative studies. There were no statistically significant differences in GMTs of anti-HAV and anti-HBsAg antibodies between the three different vaccine lots when evaluated in the pooled analysis. Furthermore, antibodies to HAV and HBsAg persisted for up to 72 months in two studies. Among adult vaccinees, age appears to have little influence on immunogenicity of the vaccine.

Paediatric Combined Vaccines: The three-dose vaccine (Twinrix™ Paediatric)demonstrated overall immunogenicity similar to that of a candidate, high-dose combined hepatitis A and B vaccine, and to the two-dose vaccine (see above), producing 100% rates of month-7 anti-HAV antibody seroconversion and anti-HBsAg antibody seroprotection. These results for the three-dose vaccine were confirmed in two noncomparative studies in individuals aged 1–15 years. Moreover, seroprotective antibody levels persisted for 36–60 months after initial vaccination.

The two-dose regimen (AmBirix™) administered at months 0 and 6 produced month-7 seroconversion to anti-HAV antibodies in all evaluable vaccinees, and seroprotection against HBsAg in 98–99% of vaccinees, in one noncomparative and two comparative studies in individuals aged 1–15 years. The corresponding month-13 seroconversion rate was 99% and seroprotection rate 97% after administration at months 0 and 12 in an extended-interval regimen. Altogether, 96–100% of vaccinees had a combined month-7 immunogenic response of seroconvertive titres of anti-HAV antibodies plus seroprotective levels of anti-HBsAg antibodies. Age <6 years versus ≥6 years, or 1–11 years versus 12–15 years, had no major influence on overall immunogenicity.

Furthermore, immunogenicity of the two-dose schedule (month 0 and 6) was similar to that of the half-strength three-dose vaccine (Twinrix™ Paediatric), with 99–100% anti-HAV antibody seroconversion and anti-HBsAg antibody seroprotection at month 7. Seroprotective antibody levels were sustained 24 months after the first vaccination with the two-dose vaccine.

Tolerability

Adult Vaccine: The combined vaccine is generally well tolerated. Adverse events were associated with 50.0–67.5% of >4500 doses of the adult vaccine in pooled data from comparative and noncomparative studies. The most common local events were injection-site pain (34.7–60.8% of doses) and redness (5.0–33.2%) and occurred markedly more often than general or systemic events such as fatigue (6.1–31.7%) and headache (2.4–25.4%). Pooled results from another database of six nonblind studies involving a total of 2440 vaccine doses confirm these to be the most frequent local and general events.

Overall, most adverse events were mild and transient, disappearing within the 4-day post-vaccination period, and fewer events were noted after the second or third, rather than first, vaccination. There were no statistically significant tolerability differences between the vaccine and a candidate, high-dose combined hepatitis A and B vaccine, or monovalent hepatitis A and B vaccines. An accelerated schedule of the vaccine (day 0, 7 and 21, and month 12) also had a tolerability profile similar to that of monovalent hepatitis A (day 0 and month 12) plus hepatitis B (day 0, 7 and 21, and month 12).

Nonetheless, several studies reported statistically significant tolerability advantages for the combined vaccine: less injection-site pain than monovalent hepatitis A vaccine (Havrix™); when administered concomitantly with monovalent typhoid vaccine (Typherix™), less injection-site pain than same-syringe, extemporaneously mixed combined hepatitis A and B vaccine plus typhoid vaccine; a lower total local symptom score than extemporaneously mixed monovalent hepatitis A and B vaccines (Havrix™ plus Engerix B™); and less injection-site pain, redness and malaise than the single-entity constituent vaccines administered simultaneously.

Paediatric Vaccines: The three-dose paediatric vaccine has a tolerability profile generally similar to that of the adult vaccine regarding the type and severity of adverse events: i.e. injection-site pain and redness, and fatigue and headache were the most frequent events reported in clinical trials; most events were mild or moderate and transient. Nonetheless, the overall incidence of adverse events was generally less with the paediatric than adult vaccine (37.0–53.9% vs 50.0–67.5% of vaccine doses). No major tolerability differences were identified between the three-dose and two-dose paediatric vaccines. However, in children/ adolescents aged 1–15 years, but not in older children/adolescents (aged 11–18 years), tolerability was significantly more favourable for the three-dose vaccine than for two doses of a candidate high-dose combined hepatitis A and B vaccine.

The tolerability profile of the two-dose vaccine (AmBirix™) largely parallels that of the three-dose adult vaccine, since the two formulations are the same. Thus, in vaccinees aged 1–15 years, the most common adverse events were injection-site pain (42.4–50.7% of doses) and redness (6.6–16.1%), and general fatigue (12.4–29.2%) and headache (11.1–18.5%). Most unsolicited adverse events were mild or moderate, and most resolved in the 30-day post-vaccination period. Only 10 serious adverse events were reported; these were considered not or probably not related to the study vaccine. No major tolerability differences were identified between two different two-dose schedules of the vaccine (months 0 and 6 vs months 0 and 12).

Pharmacoeconomic Considerations

Compared with monovalent hepatitis B vaccination or no vaccination, combined hepatitis A and B vaccination has been shown to be a cost-effective intervention in two European modelling studies in children/adolescents aged ≤15 years. Both studies considered cost-effectiveness projections (over a 30-year period) to be underestimates. In a Swiss/Austrian study, all three evaluated age groups (0–15, 1–15 and 11–15 years) demonstrated a lower overall incremental cost-effectiveness ratio (CER) for combined hepatitis A and B vaccination compared with monovalent hepatitis B vaccination. The most favourable CER (for both vaccination strategies) was obtained when vaccinating those aged 11–15 years. In a German study, compared with no vaccination, combined hepatitis A and B vaccination was predicted to prevent 57 596 new cases of hepatitis A and 45 820 new cases of hepatitis B in children/adolescents aged 1–15 years, corresponding to savings in treatment costs of DM5.1 billion.

Substituting hepatitis B vaccine with combined hepatitis A and B vaccine in US prison inmates has been shown (in a Markov model) to meet accepted standards of cost effectiveness in the US. With hepatitis A infection rates >200% the US national average, the cost effectiveness of using combined hepatitis A and B vaccine was estimated to be <$US0 per life-year saved (i.e. a reduction in health system costs). While lower rates of hepatitis A infection resulted in reduced cost effectiveness for the combined vaccine, costs (including those obtained by sensitivity analyses) remained with accepted standards.

Dosage and Administration

Each dose of combined hepatitis A and B vaccine contains 360 or 720 ELISA units of formalin-inactivated HAV (strain HM175), and 10 or 20μg of recombinant DNA, yeast-derived HBsAg, and should be injected intramuscularly into the deltoid, or into the anterolateral thigh in infants. The recommended primary vaccination schedule is two doses (one at month 0 and one after 6–12 months [AmBirix™]) or three doses (one each given at months 0, 1 and 6 [Twinrix™ Adult and Twinrix™ Paediatric]). However, an accelerated schedule of the adult vaccine administered on days 0, 7 and 21, and at month 12, is approved in a number of countries for individuals aged ≥16 years travelling to HAV/HBV endemic regions within 1 month.

Combined hepatitis A and B vaccines are not recommended for prophylaxis after mucous membrane, ocular or percutaneous (needle-stick) exposure to HBV.

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    David L. Murdoch, Karen Goa & David P. Figgitt

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Additional information

Various sections of the manuscript reviewed by: J. Beran, Department of Infectious Diseases, University Hospital, Hradec Králové, Czech Republic; H.D. Nothdurft, Abt. für Infektions- und Tropenmedizin, Universität München, München, Germany; S.K. Sarin, Department of Gastroenterology, GB Pant Hospital, New Delhi, India; S. Thompson, Department of Health, Sexual Health and Blood-Borne Virus Program, Perth, Western Australia, Australia; K. Van Herck, Centre for the Evaluation of Vaccination, WHO Collaborating Centre for Prevention and Control of Viral Hepatitis, Antwerp, Belgium.

Data Selection

Sources: Medical literature published in any language since 1980 on hepatitis-A-hepatitis-B-vaccine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘hepatitis A and B vaccine’. EMBASE search terms were ‘hepatitis A and B vaccine’. AdisBase search terms were ‘hepatitis-a-hepatitis-b-vaccine’. Searches were last updated 24 October 2003.

Selection: Studies in patients who received combined hepatitis A and B vaccine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant immunogenicity and tolerability data are included.

Index terms: Hepatitis A, hepatitis B, combined vaccine, immunogenicity, tolerability.

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Murdoch, D.L., Goa, K. & Figgitt, D.P. Combined Hepatitis A and B Vaccines. Drugs 63, 2625–2649 (2003). https://doi.org/10.2165/00003495-200363230-00008

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