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Vaccination is an important tool in hepatitis B prevention. However, several vaccine doses are required to induce long‐term protection. Several at‐risk groups have difficulties in adhering to the standard vaccination schedule.
This paper aims to review the use of accelerated hepatitis B vaccination schedules, in terms of immunogenicity and compliance.
Accelerated schedules (0.1.2.12 months) or super‐accelerated schedules (0.7.21.360 days) have been shown to result in higher proportions of healthy vaccinees reaching anti‐HBs antibody levels 10 IU/l more rapidly. A fourth completing dose is required to lift antibody levels to an equal height, as does a standard (0.1.6 months) schedule.
Accelerated schedules do also increase the uptake of hepatitis B vaccine, that is the proportion of vaccinees who receive three doses. However, completing the schedule with a fourth dose is usually more difficult than completing a standard 0.1.6‐month schedule. Several additional tools can help to increase the compliance (eg, reminder systems, outreach services and incentive schemes).
For rapid seroconversion and almost immediate protection in the short term, a (super)accelerated schedule could be used in at‐risk groups. As long‐term protection data with these (super) accelerated schedules have not been documented yet, a fourth dose at month 12 is still required. A shortened schedule (0.1.4 months) might be an alternative worth considering compared with the standard 0.1.6, as it convenes to internationally accepted minimum dose intervals and offers earlier protection. There is a clear need to study the long‐term protection and effectiveness of the primary part of (super)accelerated schedules.
In 1992, the Global Advisory Group of the Expanded Programme on Immunisation (World Health Organization, WHO) set 1997 as the target for integrating hepatitis B virus (HBV) vaccination into national immunisation programmes worldwide.1 Even if it was estimated that more than one‐half of the world's infants were still not being immunised in 1999, substantial progress in implementing that WHO recommendation has been made since. By the end of 2005, 168 countries worldwide had implemented or were planning to implement a universal HBV immunisation programme for infants and/or adolescents.2,3
Apart from the above‐mentioned universal immunisation programmes, several risk groups are targeted by hepatitis B vaccination programmes. These groups are either at increased risk of HBV infection or at increased risk of complications in case an HBV infection were to occur.4 Unfortunately, despite the longstanding existence of recommendations, it often remains difficult to reach at‐risk groups due to a combination of factors, including lack of perceived risk and the limited presence of specific healthcare programmes targeting certain risk groups (in particular sex workers, injecting drug users, and prisoners). Moreover, even if they can be reached, those who engage in high‐risk behaviour often fail to complete the required vaccination regimen for hepatitis B.5
Whenever hepatitis B immunisation programmes targeting such at‐risk groups are implemented or evaluated, the choice of the most efficient vaccination schedule is an important issue. After all, the standard hepatitis B vaccination schedule might need to be adapted, either to increase the probability of completing the vaccination in groups with limited compliance, to offer protection as soon as possible after starting the vaccination schedule, or to better fit this vaccination programme into existing vaccination or other preventive programmes in that specific at‐risk population. It is beyond doubt that any adaptations should aim to optimise the compliance to the immunisation programme, while maintaining the vaccine's immunogenicity and efficacy. Since people in these at‐risk populations most often continue to be at risk, long‐term protection against hepatitis B is highly important.
This paper aims to review the evidence on (accelerated) hepatitis B vaccination schedules for risk groups: those at increased risk of sexual HBV transmission (including men who have sex with men, sex workers, and attendees of STI clinics), injecting drug users, inmates and staff of correctional facilities and prisons, and travellers to areas of intermediate or high endemicity.
The search strategy for this review consisted of the keywords (“hepatitis B” AND vaccine* AND schedule* AND accelerate*). Multiple databases were searched: BioMedCentral, the Cochrane Library, all Evidence Based Medicine reviews (Ovid), and Medline (National Library of Medicine's PubMed online search engine and Ovid Medline). The internet search engine Google was used with the same set of keywords AND “guideline” to additionally identify a number of guidelines regarding hepatitis B vaccination.
Searches were performed in February 2007, without any restrictions (eg, with regard to the year of publication or language). Related articles were assessed, and the reference lists of the retrieved articles were also used to identify related literature.
Retrieved papers were included in this review only if they described the immunogenicity and/or compliance for a standard and/or altered hepatitis B vaccination regimen in healthy adolescents, healthy adults or one of the above‐mentioned risk groups. Papers addressing hepatitis B vaccination in groups with specific medical conditions requiring additional efforts to improve the immunogenicity of routinely used hepatitis B vaccines (eg, haemodialysis patients, liver transplant candidates, immunosuppressed patients) were not included in this review. Alterations in hepatitis B vaccination schedules included modification of vaccine dosage and shortening of the interval between vaccine doses.
Worldwide, the standard schedule for vaccination of healthy children, adolescents and adults against hepatitis B consists of three doses, given according to a 0.1.6‐month vaccination schedule. However, the timing of the third dose allows substantial flexibility. The US Centers for Disease Control and Prevention recommend for adolescents and adults a minimal interval of 16 weeks between the first and the third dose of hepatitis B vaccine (and 8 weeks between dose 2 and dose 3), which allows the schedule to be shortened to 0.1.4 months. Conversely, in case the administration of the third dose were to be delayed, the complete schedule does not need to be restarted.6
Testing to determine antibody responses is not routinely recommended after routine vaccination of infants and adolescents. However, when feasible, knowledge of response to vaccination is important in the following groups: (1) all above‐mentioned risk groups; (2) persons at risk of occupational HBV exposure; (3) infants born to HBsAg‐positive mothers; (4) immunocompromised persons; and (5) sexual partners of HBsAg‐positive persons. Testing for anti‐HBs should be performed by a method that allows determination of whether the anti‐HBs concentration is 10 IU/l. Adults should be tested 1–3 months after completion of the vaccination series. Persons found to be antibody‐negative after the primary series should be referred for appropriate follow‐up.7 Lifelong protection is assumed in healthy, fully vaccinated infants, children, adolescents or adults—the last, however, should be tested after the complete vaccination series, to demonstrate a seroprotective anti‐HBs level.8 Seroprotection is defined as achieving an anti‐HBs titre above or equal to 10 IU/l, measured 1–3 months after a completed immunisation schedule (ie, 0.1.6 or 0.1.2.12 months).
The need for accelerated vaccination schedules against hepatitis B is well recognised for specific at‐risk groups. Several schedules have been investigated to enhance the compliance or to reach protective levels of antibodies earlier without cutting on the immunogenicity of hepatitis B vaccination. In high‐risk situations, where one aims to offer protection against hepatitis B as rapidly as possible, the following alternative vaccination schedules may be considered: either 0.1.2.12 months or 0.7.21.360 days. It should be noted that both accelerated schedules require the administration of a fourth dose of vaccine, 1 year after starting the vaccination. The administration of this fourth dose of hepatitis B vaccine in case an accelerated schedule is used is consistently present in a number of recommendations and guidelines from both national and international Public Health Organisations, and organisations of clinicians, in several countries.6,7,9,10,11,12,13,14,15,16
A complete vaccination course in healthy infants, children, and adolescents results in seroprotective anti‐HBs levels in over 95% of vaccinees. In adults below the age of 40, this is slightly lower (yet still more than 90%), to reach 65–75% by the age of 60 years. Decreased vaccine response is associated with smoking, obesity, genetic factors, chronic diseases and immune disorders.4
During the vaccination course, 30–55% of healthy adults below the age of 40 years reach the seroprotective anti‐HBs level after the first dose, mounting to 75% after the second dose and over 90% after the third dose.4
Pre‐exposure hepatitis B vaccine efficacy studies in several high‐risk groups have demonstrated an overall efficacy of 80–100%, with nearly 100% efficacy in persons who developed a seroprotective anti‐HBs response (10 IU/l).4
Few studies have examined the use of accelerated hepatitis B vaccination schedules in adolescents. Nevertheless, since the immunogenicity of many vaccines, including hepatitis B vaccines, is higher in younger persons, the results of studies in healthy adults can safely be extrapolated to younger age groups.4
In a study by Chowdhury et al, 100% of vaccinated adolescents reached an anti‐HBs level 10 IU/l, 1 month after the primary part of an accelerated vaccination schedule (0.1.2 months), with two different vaccines.17 Wilkinson et al described similar results in a small group of high‐risk youth.18 In another study in healthy children, Bosnak and co‐workers concluded that 1 month after administering the primary part of a super‐accelerated schedule (0.7.21 days) similar rates of anti‐HBs levels 10 IU/l were reached, when compared with the standard 0.1.6‐month schedule. However, the proportion of vaccinees attaining 10 IU/l was higher within the first 2–3 months after dose 1. No data on the magnitude of anti‐HBs levels were reported.19 Cassidy et al studied a shortened standard schedule (0.2.4 months), which resulted in a similar seroprotection rate as the standard schedule (0.1.6 months) 1 month after completion, but with remarkably lower antibody levels.20
Jilg et al clearly demonstrated in a study comparing a primary part of an accelerated (0.1.2 months) schedule with a standard (0.1.6 months) and a prolonged vaccination schedule (0.1.12 months) that a longer interval between the second and the last dose of hepatitis B vaccine resulted in higher anti‐HBs levels.21 Scheiermann et al reported similar seroprotection rates obtained by the standard (0.1.6 months) and the accelerated (0.1.2.12 months) vaccination schedule, even up to 4 years after the first dose. The accelerated schedule (including the fourth dose) yielded higher antibody levels.22 A study by Marchou et al comparing a super‐accelerated 0.10.21.365 days to the accelerated 0.1.2.12‐month schedule showed a more rapid immune response to the super‐accelerated schedule (after 1 month), yet higher antibody levels after three doses when the intervals between doses were larger.23
Other studies using the first three doses of an accelerated vaccination schedule concluded that seroprotection after the vaccination series was comparable with that obtained by the standard schedule. Accelerated schedules resulted in higher proportions reaching 10 IU/l between 3 and 6 months after the first dose; however, the antibody levels after three doses were markedly lower than with the standard schedule.24,25,26,27,28
With the primary part of different super‐accelerated vaccination schedules (three doses given within 3–4 weeks' time) the proportion reaching 10 IU/l after the vaccination series is comparable with that obtained after the standard schedule, while this proportion is higher within the first 2–3 months after the first dose. Yet again, super‐accelerated schedules result in lower anti‐HBs levels after three vaccine doses.25,26,29,30,31
The immune response to hepatitis B vaccination is known to decrease with increasing age. Both Rosman and Gellin reported a beneficial effect of increasing the vaccine's antigen dosage in adults over 40 years of age.32 The use of an accelerated schedule with a high‐dose vaccine was shown to induce higher seroprotection levels compared with the standard schedule in a population of alcoholic older subjects.33
Travellers form a very specific at‐risk group; they often have a very limited time to start a vaccination schedule. Moreover, completing a hepatitis B vaccination regimen, being at 6 or 12 months after the first dose, is often neglected. Nevertheless, most travellers are healthy persons. The above‐mentioned results thus also hold for travellers.34 This has been confirmed in two recent reviews.35,36
Lugoboni et al found a similar immunogenicity as compared with the general population, using the combined vaccine according to a standard (0.1.6‐month) vaccination schedule against hepatitis A and B in a population of drug users.37
Quaglio et al compared a 0.1.2 to a standard 0.1.6‐month schedule in heroin users; they found a significantly lower proportion reaching the 10 IU/l antibody level after three doses with the accelerated schedule (67 vs 92%).38
Several studies have reported being able to administer three doses of hepatitis B vaccine to a higher proportion of the population targeted, when an accelerated or a super‐accelerated schedule was used, at least the primary part of it. Unfortunately, few of these studies report immunogenicity data; this is mainly due to the difficulties to administer three vaccine doses, and thus the low proportion that can actually be tested afterwards.39,40,41,42,43,44,45,46
A recent paper that did report immunogenicity data studied a shortened standard schedule (0.1.4 months) as an alternative option, in a setting (sex workers) where other strategies are used to improve the compliance. Even if the 0.1.4 months schedule failed to significantly improve the compliance, it offered equal protection within a shorter interval.47
Rogers and Lubman reported that the use of a super‐accelerated schedule in an outreach programme had a positive impact on the compliance of a population of young drug users.48
Wright et al described the vaccine uptake in a population of homeless drug users in a single primary care centre. The standard schedule (0.1.6 months) that was offered in 1999 changed to the primary part of a super‐accelerated 0.7.21‐day vaccination schedule in 2000. As a result, the uptake of hepatitis B vaccination increased once the vaccination regimen was introduced, and completion rates were even seven times higher with the super‐accelerated schedule.49
Christensen et al showed that a super‐accelerated schedule resulted in a significantly higher proportion of vaccinated prisoners with intravenous drug use, and a higher efficacy. Vaccination with a 3‐week schedule in prison reached a higher proportion with anti‐HBs 10 IU/l (measured at day 210) than what could have been obtained with a standard 0.1.6‐month schedule.50
This review aimed to discuss the preferred vaccination schedules for vaccinating risk groups against hepatitis B, trying to balance the immunogenicity of the vaccine and the compliance of the vaccinees.
Indeed, there is substantial evidence that accelerated and super‐accelerated hepatitis B immunisation regimens offer a clear benefit: a larger proportion of vaccinees will reach an anti‐HBs level 10 IU/l within the first months after the first vaccine dose. However, this favourable effect is rather short‐lived; the standard (0.1.6 months) vaccination schedule induces comparable seroprotection from month 6 after the first dose onwards. Moreover, the standard schedule results in higher antibody levels; this effect is even stronger when the administration of the final dose is scheduled at month 12.21 Therefore, with regards to immunogenicity, the (super)accelerated schedule should strictly be reserved for those persons for whom protection as early as possible is desirable (including postexposure prophylaxis), or for travellers leaving within a month.9,36,51 Offering the fourth dose would guarantee a long‐term protection equal to what is known for the traditional schedules (0.1.6 or 0.1.2.12 months).
Another benefit of the (super)accelerated schedules is the improved uptake of hepatitis B vaccine in a number of at‐risk groups who are difficult to stay in touch with over a longer period of time. Studies in drug users, STI clinic attendees, sex workers and so on have demonstrated that there is a larger proportion of vaccinees who receive three doses of hepatitis B vaccine when a (super)accelerated schedule is offered. As shown in table 22,, this is especially the case in settings where the coverage of the third dose of the standard 0.1.6‐month schedule is very low (eg, homeless drug users, etc). This defines another situation where a (super)accelerated schedule could be chosen for reasons of compliance.
However, offering only the primary part of the accelerated schedules also has a downside: the final anti‐HBs levels are markedly lower, compared with schedules with a larger interval between the first and the last dose of hepatitis B vaccine. On top of that, the groups who would benefit from the more rapid protection or improved compliance offered by the accelerated schedules most often are at continuous risk or—in the case of travellers—are likely to repeat their risk over the years to come. Therefore, these groups would also benefit from long‐term protection.
Even if the current consensus regarding the need for hepatitis B booster vaccinations recommends relying on underlying cellular immunity induced by hepatitis B vaccines, rather than on persistence of antibodies alone, the consensus statement on long‐term (lifetime) protection against hepatitis B is based on data from healthy, fully vaccinated persons. When adults are concerned—which most often is the case in these at‐risk groups—the confirmation of an adequate internationally accepted seroprotective immune response (anti‐HBs 10 IU/l) after a complete series of hepatitis B vaccine is recommended.8 As of today, the terms “fully vaccinated persons” and “complete vaccination series” still refer to either the standard schedule (0.1.6 months) or the accelerated (0.1.2.12 months) or super‐accelerated schedule (0.7.21.360 days) including the fourth dose after 12 months.6,7,9,10,11,12,13,14,15 Even if an adequate immune response after the first three doses of a (super)accelerated hepatitis B vaccination schedule might be sufficient to also offer long‐term protection (there is as yet insufficient scientific evidence to support this), this could become subject to further research. Based on the presently available data, we cannot conclude that long‐term protection against hepatitis B is warranted in persons who only received the first three doses of an accelerated schedule, either 0,1,2 months or 0,7,21 days, even if they showed an anti‐HBs level 10 IU/l 1–3 months after the third dose. Independently of an eventual risk of hepatitis B infection before completion of the vaccination schedule, long‐term protection needs to be evidenced after a (super)accelerated schedule.52
In these settings of risk group vaccination, the vaccination schedule should therefore rather be chosen by balancing the need for more rapid protection as compared with that offered by the standard 0,1,6‐month vaccination schedule, with the need for offering long‐term protection to persons who continue being at risk. That choice will be affected by the additional cost and the feasibility of offering a fourth vaccine dose.
There is a clear need to study the possible long‐term (ie, 10 years and beyond) efficacy and protection of the three‐dose (super) accelerated schedules. However, such studies are difficult to conduct in the at‐risk groups—for example, sex workers. First, in case one managed to consistently follow‐up at‐risk persons over a number of years, it would be unethical not to offer them the fourth dose of hepatitis B vaccine. Second, in such an at‐risk setting, there is a higher probability of intermediate exposure to hepatitis B virus, and thus of natural boosting. However, long‐term observational studies could be considered in travellers or healthcare workers who did not receive their fourth dose and who could more easily be recalled compared with the setting of sex workers, for example.
As long as evidence demonstrating this long‐term protection is lacking, a more “compact” standard schedule (ie, 0.1.4 months) might be an option worth considering, to maximise both seroprotection rates and compliance to offer early long‐term protection with the least number of doses.47 Confirmation of these observations is welcomed in further studies, comparing seroprotection with this compact schedule. After all, most at‐risk groups are at continuous risk and thus clearly benefit from long‐term protection.
To further improve the compliance of difficult‐to‐reach at‐risk groups, other strategies (eg, reminder systems, outreaching activities, incentive schemes, etc) need to be considered.42,45,46,47,48,53,54,55,56,57,58,59,60,61 Additionally, the value of an alternative vaccine giving equivalent immunogenicity with two doses only would be very useful in at‐risk populations. The venue of new adjuvants could support these alternative approaches.
EL and KVH performed the literature searches and prepared a draft manuscript. PVD was involved in interpreting the results and final editing of the manuscript.
HBV - hepatitis B virus
WHO - World Health Organization
Conflict of interest statement: EL and PVD are employees of the University of Antwerp. KVH is a Postdoctoral Fellow of the Research Fund Flanders (FWO grant no. 1.2.695.07N00). PVD and KVH have been principal investigators of vaccine trials for several vaccine manufacturers, for which the University of Antwerp obtains research grants.