- Top of page
- Declaration of interests
Background. Protection against hepatitis A virus (HAV) in the elderly is becoming more important as more senior travelers visit areas of high HAV endemicity, and less have protective antibodies acquired after natural infection during childhood. This study assessed the immunogenicity and safety of hepatitis A vaccine in elderly compared to young adults.
Methods. In this open, uncontrolled study, subjects of 18 to 45 years or ≤50 years of age received two doses of aluminum-free, virosomal HAV vaccine, Epaxal® (Berna Biotech Ltd, formerly Swiss Serum and Vaccine Institute, Bern, Switzerland) 12 months apart.
Results. After both the basic and the booster doses, geometric mean titers (GMT) for anti-HAV antibodies were 1.7-fold higher in subjects younger than 45 years compared with those ≤50 years of age. The proportional increase in GMT after the booster dose, however, was similar in younger and older subjects. Seroprotection (≤20 mIU/mL) rates in the younger and older subjects were 100 and 65%, respectively, after the first vaccination and 100 and 97%, respectively, after the booster dose. Systemic and local adverse events were mainly mild and short-lived.
Conclusion. These data show that HAV virosomal vaccine (Epaxal®) is well tolerated and immunogenic in elderly subjects. The clinical relevance of lower seroconversion rates after the primary dose is unknown in this population of travelers.
Although hepatitis A virus (HAV) infection is generally asymptomatic or subclinical in young children,1 the likelihood of symptomatic disease increases with age. Adults older than 40 years are at significantly greater risk than younger patients of serious complications, including death. In addition, while the overall case fatality rate of hepatitis A is estimated as 0.15% in the general population, it may exceed 2% in patients older than 40 years.2–4
The average age of travelers from areas of low HAV endemicity to areas of high HAV endemicity is more than 40 years,5–7 but the efficacy of HAV vaccines in the elderly subjects is not well documented. Although several studies have examined the efficacy of HAV vaccination in subjects older than 40 years,8–12 only two reports have so far addressed the efficacy of HAV vaccination in subjects older than 60 years, both using a combined hepatitis (A and B) vaccine.13,14 Not all these studies used the current dosing regimens, and some had methodological limitations, but in general, the immune response to HAV vaccination appears to be lower in elderly subjects compared with younger people.8
More recently, immunopotentiating-reconstituted influenza virosomes have been developed as an alternative to aluminum for delivery of antigen. Epaxal® (Berna Biotech Ltd, formerly Swiss Serum and Vaccine Institute, Bern, Switzerland) is the first commercially available, aluminum-free vaccine, and consists of inactivated HAV bound to virosomes by electrostatic forces.15 This vaccine has proved to be highly immunogenic and safe in adults and children16–19 and to cause significantly fewer local adverse events than aluminum-adsorbed vaccine.20,21
The objective of this study was to assess the immunogenicity and safety of the virosomal hepatitis A vaccine in subjects aged ≤50 years, as the clinical trials conducted during the development of this vaccine enrolled mainly young adults.
- Top of page
- Declaration of interests
This prospective, open, uncontrolled, single-center study compared safety and immune response of a virosomal hepatitis A vaccine in elderly subjects with that in a group of young adults. Written informed consent was obtained from all participants, and the study was conducted in full compliance with the Amended Declaration of Helsinki III.
The study enrolled female and male adults aged 18 to 45 years (younger group) and 50 years or older (elderly group). Subjects were excluded if they were seropositive for anti-HAV antibodies (≤20 mIU/mL), had received a previous vaccination against HAV, or had been immunized with any other vaccine(s) within 4 weeks before or after the baseline evaluation and study basic vaccination. The elderly subjects were screened for anti-HAV seronegativity prior to enrollment. Immunizations with another vaccine were permitted during the remaining duration of the study, provided that there was an interval of at least 4 weeks before and after the booster dose. Other exclusion criteria were acute illness, history of severe atopy, simultaneous treatment with immunosuppressants, immunodeficiency (including neoplasms and HIV seropositivity), pregnancy, or lactation. Subjects were also excluded if they had received immunoglobulins or blood transfusion within the preceding 3 months. The younger participants were to be stratified into equally sized groups of males and females. All the subjects received basic vaccination with the virosomal hepatitis A vaccine on day 1 and a booster dose after 12 months. The vaccine (0.5 mL) was injected intramuscularly into the deltoid muscle of the left upper arm.
Blood samples were obtained at 0 to 7 days before the basic vaccination: at 28 days, 6 and 12 months (before the booster dose) after the basic vaccination, and 1 month after the booster dose for determination of serum anti-HAV antibodies by an automated enzyme immunoassay (Enzymun-Test®; Boehringer Mannheim, Mannheim, Germany). Serological testing was performed at the University Children's Hospital, Basel, Switzerland. Titers were expressed as anti-HAV antibody concentrations in mIU/mL relative to the international reference anti-HAV immune serum (WHO, Geneva, Switzerland) supplied by the manufacturer.
All adverse events that occurred during the trial were recorded. In addition, the vaccinees recorded solicited local (induration/hardness, pain/tenderness, redness of more than 5 mm diameter, and tumefaction/swelling) and solicited systemic (arthralgia, headache, nausea, fatigue, and anorexia/loss of appetite) adverse events for 4 days after each vaccination. The vaccinees graded the severity of adverse events on a 4-point scale ranging from “0 = none” through “1 = mild” (not interfering with daily activities), “2 = moderate” (interfering with daily activities), and “3 = severe” (preventing normal daily activities). The relationship of systemic adverse events to the trial vaccinations was determined by the investigator; local adverse events were considered “definitely” related to the trial vaccinations. Body temperature was measured on the days before the basic vaccination and the booster dose at 12 months. Vaccinees recorded their body temperature for 4 days after each vaccine dose.
The primary study end point was the anti-HAV antibody titer. A titer of 20 mIU/mL or above was considered protective.11 However, since there is discussion in the literature that a level of 10 mIU/mL or above may be protective,22 this was used as a secondary end point, together with the incidence and duration of adverse events and increased body temperature.
Immunogenicity data were evaluated by descriptive statistics, including 95% confidence intervals (CI) for the geometric mean titers (GMT) calculated from the log-transformed titer values and by applying a t-test. A linear regression analysis of log10 postbooster titers versus age was also performed. It was considered that the planned numbers (60 younger adults and 40 elderly people) were sufficient to meet the objectives of the study.
Adverse events and body temperature were evaluated descriptively and in terms of rates.
- Top of page
- Declaration of interests
The results of this study confirm that, although valid priming was achieved in both age groups after the virosomal hepatitis A vaccine administration, the titers of anti-HAV antibodies and the proportion of subjects seroprotected (≤20 IU/mL) after basic vaccination were lower in those older than 50 years than in younger subjects. This difference should be considered with caution due to the rather limited sample size of elderly people and hence the low statistical power. In the 30 subjects older than 50 years, 60% were seroprotected at 12 months after the basic vaccination, and all subjects except one were seroprotected by 1 month after the booster dose.
Similarly, low seroprotection rates have been reported after primary doses of aluminum-adsorbed hepatitis A vaccines, such as 70% in volunteers >40 (mean 46.4) years old 1 month after priming.12 A review of worldwide experience with single doses of an aluminum-adsorbed HAV vaccine (Vaqta®, Merck & Co., Whitehouse Station, NJ, USA) also suggests that the efficacy of this type of vaccine may decrease with increasing age.23
In a retrospective pooled analysis of five clinical trials of the combined HAV and hepatitis B virus aluminum-adsorbed vaccine Twinrix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), a similar decrease in immune response was observed with age, though 1 month after the three-dose vaccination schedule, all subjects older than 50 years (including those older than 61 years) were seroprotected (anti-HAV titer above 20 mIU/mL).14 However, in another retrospective study of unselected subjects in the community, only 63% of subjects older than 60 years were seroprotected 1 to 36 months after completion of the vaccination schedule.13 It is not clear how closely the findings with the combined vaccine can be related to results of vaccination with monovalent HAV vaccines.
There is evidence from studies with aluminum-adsorbed HAV vaccines that the immune response may develop more slowly in older subjects than in younger ones,11,12 suggesting that the initial dose should be given longer before travel than is often the case.8 Whether the administration of a second priming dose prior to travel-associated exposure would ensure full protection in elderly subjects is not known.
The above considerations may, on the other hand, be too conservative. Indeed, when using a threshold of ≤10 mIU/mL for seroprotection, as used in several previous studies, the rate in our elderly group was 97% instead of 60% prior to the booster dose at month 12. Furthermore, it is established that the booster dose of HAV vaccines in adults can be administered well beyond the recommended 6 to 12 months after the primary dose without compromising the booster response and this up to 8 years after priming.24–26 This phenomenon is thought to be indirect evidence for immune memory.27 Although not designed specifically for elderly people, data of the booster interval study with the virosomal hepatitis A vaccine24 show that the titers achieved after boosting are, in 115 travelers aged 20 to 70 (mean, 45) years, not correlated with age (linear regression analysis; r= 0.1, p= 0.3); ie, the booster response was the same across all ages (Berna Biotech, data on file). This fits well with the experience in the present study, where the proportional increase in GMT of anti-HAV antibodies after the booster dose was within a close range for all age groups, suggesting that the elderly people had a immune response to the booster dose comparable to that in the younger subjects, even though the initial response was less.
There are, with the exception of two field trials in children,28,29 to our knowledge, no human data demonstrating protection from natural infection in adults or elderly people, following a single dose of HAV vaccine. Nevertheless, the immune response achieved in elderly people after one dose might still be sufficient to protect against clinical disease, as one can assume from the fact that vaccine failures have so far not been a problem with any HAV vaccine in elderly people.
The virosomal hepatitis A vaccine was well tolerated by all age groups in the present study, and local tolerability appeared better in the older age groups than in the younger, as is seen in most of the vaccine trials.
In conclusion, this study shows that the aluminum-free, virosomal vaccine Epaxal® is an effective and well tolerated HAV vaccine in elderly subjects. Despite the fact that the primary response to the vaccine was lower in the elderly group, valid priming was obtained in these subjects, and seroprotection was achieved in all but one subject older than 60 years after the booster dose. Subjects older than 50 years may benefit from a second dose before traveling to ensure protection against HAV infection, with the risk of an impaired long-term protection if the interval between the two doses is too short, and no booster is given. To establish clear pretravel recommendations for hepatitis A vaccination in elderly people, the need for such an additional primary dose merits further investigation.