1. Top of page
  2. Abstract
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Declaration of Interests
  7. References


Increasing numbers of travelers using immunosuppressive drugs visit hepatitis A endemic countries. Data on protection rates after hepatitis A vaccination in this group are scarce.


In this retrospective study, records of subjects with hepatitis A serology taken after vaccination were searched for in travel clinic databases. Relation between immunosuppressive drug use, age, gender, and time between vaccination and serology was evaluated.


Seroprotection rates within 4 weeks after primary vaccination (50%) are lower than after 4 weeks (64%). After the complete series of two vaccinations seroprotection rates reach 95% although success depends on the immunosuppressive drug being used. Subjects under anti-TNF alpha treatment have significantly lower seroprotection rates than subjects using classical immunosuppressive drugs after the second vaccination. There is no influence of age or gender on seroprotection rates.


Last-minute vaccination in subjects using immunosuppressive medication is not reliable, only 60% of our subjects had a protective antibody level after a single vaccination. When serology was done within 4 weeks after a single vaccination, seroprotection rates were only 50%, after 4 weeks this number rose to 64%. When persons visit a travel clinic in time for a complete vaccination series, satisfactory seroprotection rates can be reached. Seroprotection rate depends on the drug being used, persons using anti-TNF alpha are less protected.

Since a vaccine for active immunization became available in 1992,[1] hepatitis A virus (HAV) infection has become a preventable disease. In contrast to some other parts of the world,[2] we do not have a routine vaccination schedule for HAV for infants in the Netherlands; vaccination is recommended for travelers aged ≥1 year to hepatitis A endemic countries,[3] for persons who are at increased risk of infection within the Netherlands, and for people with liver diseases like chronic hepatitis B or C infection.[4] Hypersensitivity to any component of the vaccine or severe febrile illness are contra-indications. Immune responses to hepatitis A vaccination in healthy people are excellent,[5-9] but serology is recommended when a reduced response to vaccination is expected due to an altered form of administration or immunodeficiency caused by disease or therapy.[3]

Since increasing numbers of travelers using immunosuppressive medication visit countries for which vaccination is recommended,[10] the need for reliable information on immunogenicity of vaccines in this group grows. The purpose of this study is to explore the effectiveness of hepatitis A vaccination, measured as seroprotection rate, in persons who are treated with different types of immunosuppressive medication.

Subjects and Methods

  1. Top of page
  2. Abstract
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Declaration of Interests
  7. References

In this retrospective study, databases from the years 2005 up to 2012 of five municipal public health travel clinics and one hospital-based travel clinic were screened for records including hepatitis A serology. Reasons for antibody testing were evaluated. Records of persons vaccinated intramuscularly with monovalent hepatitis A vaccine and treated with systemic corticosteroids (prednisolone equivalent of >10 mg daily for at least 2 weeks or >700 mg consecutive), methotrexate, azathioprine (or 6-mercaptopurine), other cytostatics, anti-TNF alpha, other systemic immunomodulating drugs or a combination of these drugs were further evaluated. In case of combination therapy which included anti-TNF alpha this was considered the most potent drug; combined therapy of corticosteroids with methotrexate or azathioprine was counted for either methotrexate or azathioprine. Subject characteristics, total number of hepatitis A vaccines received, date(s) of vaccination, and the date of antibody testing were recorded. Except for persons using immunosuppressive medication, all persons who according to Dutch national guidelines require hepatitis A serology after vaccination (total body radiation therapy, congenital, or acquired immunodeficiency) were excluded. Also HIV-seropositive persons, subjects with a primary hepatitis A vaccination before the start of immunosuppressive therapy and persons with severely impaired humoral immunity were excluded. Subjects were either counted for in the single vaccination group or complete vaccination series. Labs determine qualitative or quantitative antibody titers, but always provide collaborating travel clinics with qualitative results analyzed by one of the following systems: AxSYMMicroparticle Enzyme Immunoassay (MEIA; Abbott, Chicago, IL, USA), Architect Chemiluminescence Microparticle Immuno Assay (CMIA; Abbott), ADVIA Centaur Chemiluminescent Immunoassay (Siemens, Erlangen, Germany), and VIDAS Enzyme Linked Fluorescent Immunoassay (BioMeriéux, Marcy l'Etoile, France).

Statistical Analysis

To evaluate the effect of anti-TNF alpha as a group, subjects using these drugs were combined and compared with subjects using classical anti-rheumatics and a group using other immunosuppressive drugs (Table 1). To evaluate whether age is of influence on response to vaccination, three age groups were formed, young (<40 years), middle aged (40–60 years), and elderly (≥60 years). Associations between protective titers after vaccination and other variables were examined using the two-sided χ2 test. A multivariate logistic regression model was used to adjust for age group, gender, and medication group. All calculations were performed using spss version 20.0.

Table 1. Baseline characteristics
 Anti-TNF groupaClassic anti-rheumaticsbOther immunosuppressivesc 
Charcteristicsn = 31n = 123n = 19p-Value
  1. a

    Anti-TNF factor α, n = 31 (18%).

  2. b

    Corticosteroids, n = 26 (15%); methotrexate, n = 57 (33%); azathioprine, n = 40 (23%).

  3. c

    Cytostatics, n = 8 (5%); leflunomide, n = 2 (1%); interferon, n = 2 (1%); tacrolimus, n = 3 (2%); cyclosporine, n = 2 (1%); natalizumab, n = 1 (1%); tocilizumab, n = 1 (1%).

  4. d

    Two-sided χ2 test for anti-TNF versus classic anti-rheumatics versus other immunosuppressives.

  5. e

    Kruskal–Wallis for anti-TNF versus classic anti-rheumatics versus other immunosuppressives.

Women (%)6163580.923d
Age, median (range), years50 (22–76)49 (19–78)51 (20–61)0.644e
Single vaccination (%)7164790.391d

Ethical Issues

For this non-interventional retrospective study no ethics committee approval was required.


  1. Top of page
  2. Abstract
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Declaration of Interests
  7. References

Between January 2005 and June 2012, in total 740 records of hepatitis A serology were documented. Reasons for antibody testing before or after vaccination were subcutaneous vaccination (16%), possible pre-vaccination exposure to HAV (46%), immunosuppressive medication in combination with HAV vaccination (23%), and others including serology after hepatitis A and B bivalent vaccine, prior vaccination status, and unclear course of events (15%). One subject was treated with rituximab and therefore excluded. For the 173 subjects that met the inclusion criteria (62% female, median age 50 years, range 19–78 years) methotrexate was the drug most frequently taken (33%) followed by azathioprine (23%), anti-TNF alpha (18%), corticosteroids (15%), cytostatics (5%), and others (6%). Sixty-seven percent of the individuals was tested after a single vaccination and 33% after two doses with an average interval of 73 weeks (range 19–430 weeks). The average interval between the last vaccination and serology was 16 weeks with a range of 2 to 394 weeks. No significant baseline differences in age, gender, and number of vaccinations were observed between the three drugs groups (Table 1).

Seroprotection Rates

Antibody titers taken less than 4 weeks after primary vaccination resulted in seroprotection rates of 50%. When samples were taken after 4 weeks or more, seroprotection rates increased to 64%, although this difference was not significant (p = 0.146). The overall seroprotection rate after a single vaccination was 60%. After the second vaccination seroprotection rates for the whole group reached 95%. Of the subjects using anti-TNF alpha, 46 and 79% were protected after a first and second vaccination, respectively. For subjects using classical anti-rheumatic drugs seroprotection rates were 62 and 98%, and in the group using other immunosuppressive drugs seroprotection rates were 67 and 100% (Figure 1). The subject's age is not of significant influence on seroprotection rates. Seroprotection rates in the youngest age group were 57 and 95% after one and two vaccinations, respectively. For the second age group rates were 56 and 92%, and for the oldest group 68 and 100% (Figure 1).


Figure 1. Seroprotection rates after a single vaccination and after a series of two vaccinations. Anti-TNF alpha: anti-tumor necrosis factor α therapy. Classical anti-rheumatics: corticosteroids, methotrexate, and azathioprine. Other: immunosuppressive medication, not anti-TNF alpha, or classical anti-rheumatics. *p-Value from two-sided Pearson's χ2 test between immunosuppressive medication used after two vaccinations; 0.045. p-Value for age groups after two vaccinations; 0.555.

Download figure to PowerPoint

The frequency of anti-TNF alpha usage per age group was higher for the younger than for the older groups: 26% (9/35) for the youngest, 20% (10/50) for the middle group, and 10% (3/31) for the oldest group after one vaccination (p = 0.245), and 20% (4/20), 13% (3/24), and 15% (2/13) after a complete vaccination series (p = 0.793). Multivariate logistic regression analysis with age group, gender, number of vaccinations, and anti-TNF alpha versus no anti-TNF alpha usage as independent variables, showed that only the use of anti-TNF alpha versus other immunosuppressives [odds ratio (OR) = 0.40, 95% confidence interval (CI): 0.16–0.99] and a second vaccination given or not (OR = 13.01, 95% CI: 3.76–45.04) were of significant influence on seroprotection rates.


  1. Top of page
  2. Abstract
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Declaration of Interests
  7. References

For a number of disorders the effect on the immune response after hepatitis A vaccination has been studied before; seroconversion rates in HIV-seropositive persons are significantly lower than in HIV-negative men, with the CD4 count being related to response rate.[11-13] As far as we know, this is the first study to evaluate the effect of hepatitis A vaccination in a population using immunosuppressive drugs. The monoclonal antibody rituximab, aimed against B-lymphocytes and thus influencing humoral response is known to result in a reduced antibody response after influenza vaccination.[14-17] For other immunosuppressive drugs only some data on response to influenza vaccination are available. In patients treated with anti-TNF alpha, a good serological response was found, equal to, or slightly lower than in control groups.[18-20] Vaccination while using methotrexate induces satisfactory humoral responses,[19, 21] as well as vaccination under corticosteroid treatment[19, 22] or azathioprine treatment.[23]

Our findings indicate that satisfactory anti-HAV titers after vaccination are also acquired despite the use of immunosuppressive drugs. Seroprotection rates after a complete vaccination scheme depended on the drug used. Seventy-eight percent was protected when anti-TNF alpha was used and 98% when classical anti-rheumatics were used. Since many travelers visit the travel clinic shortly before departure the response after a single vaccination is also relevant. As expected, seroprotection rates are lower than after a complete series, 60% versus 95% (p < 0.05) for the whole group, 67% versus 98% (p < 0.05) for the classical anti-rheumatics group, 46% versus 78% (p > 0.05) for the anti-TNF alpha group, and 67% versus 100% (p > 0.05) in the group using other immunosuppressives. In only 50% of the subjects a protective antibody titer was found within 4 weeks after a single vaccination, after 4 weeks this number rose to 64% (p > 0.05). These figures suggest that last-minute vaccination is not safe when travelers use immunosuppressive medication. Although passive immunization has disadvantages, including a very low risk for blood borne conditions,[24] higher costs in repeated exposure and a maximum protection of 13 weeks,[25] it protects effectively against clinical symptoms of hepatitis A infection and is therefore recommended in addition to the first dose of vaccine for the last-minute immunosuppressed traveler in some countries. In other countries, like Belgium and France, immunoglobulins are not registered for pre-exposure HAV immunization.

One might expect to see lower seroprotection rates after a single vaccination for the older age group, eg, based on a slower developing immune response.[26] In our study, seroprotection rates after one or two vaccinations did not differ significantly between the three age groups. Multivariate logistic regression indicates that the less frequent use of anti-TNF alpha in the older group does not explain the relatively high seroprotection rate in this group. Relatively high seroprotection rates might be explained by a bigger proportion of that group having naturally acquired antibodies against hepatitis A.[27] Since we do not have pre-vaccination titers, and due to the lack of power of this study, no firm conclusions can be drawn on seroconversion rates related to age.

A retrospective study like this always has its limitations. We know that immunogenicity in immunocompetent subjects is excellent. Clinical studies in this group demonstrate seroconversion rates of 79% on day 13, 86.3% on day 15, 95.2% on day 17, and 100% on day 19 after a single dose Havrix 1440 (GlaxoSmithKline UK, Middlesex, UK).[28] In our study we did not have a pre-vaccination antibody titer, so no comment on immunogenicity of the vaccination can be made. Only the percentage of persons protected after vaccination can be given. In travel health care this is not a huge problem because the aim is a protected traveler.

Further studies are needed to evaluate the best method to protect the immunosuppressed traveler. In HIV-infected persons an alternative three dose scheme induced a significantly higher antibody titer and a non-significantly higher seroconversion rate compared to the standard two dose scheme.[13] This vaccine scheme might also be useful in travelers using immunosuppressive medication and attending a travel clinic well before departure, but to our knowledge no studies have been conducted evaluating this scheme in this group.

While we have studied the seroprotection rate after hepatitis A vaccine we cannot conclude with certainty that in these patients insufficient antibody titers correspond with a lack of clinical protection. Documenting vaccine failures in immunocompromised travelers would bolster our results. On the basis of this study we can formulate the following advice for the professional in travel health care:

  1. Try to catch the (potential) traveler before he is taking the immunosuppressive drugs. Identifying the potential traveler is the most difficult part, but there are possibilities to do so. In our hospital for example, specialists prescribing immunosuppressive medication are trained and reminded by protocol to advise patients with traveling plans to visit a travel clinic.
  2. For the (potential) traveler already using immunosuppressive medication: for now offer a vaccination series with, if possible, post-vaccination serology. Protection rates after one vaccination are so low that we cannot assure the immunocompromised travelers that they will be protected during travel without serology testing. If more data become available post-vaccination titer might not be necessary for subjects using certain immunosuppressive drugs, eg, methotrexate, azathioprine, or corticosteroids.
  3. For the last-minute traveler already using immunosuppressive medication: give active vaccination together with passive immunization before this specific journey. If immunoglobulins are not available, be aware that seroprotection is low after one vaccination. When there is more interest in traveling to HAV endemic areas you can complete the vaccination series and do serology afterwards, if available.

Take Home Message

To ensure protection against hepatitis A in your immunocompromised patient a complete vaccination series is recommended before traveling. Alternatively, consider giving the first dose of vaccine with immunoglobulins in immunocompromised patients traveling last-minute to endemic areas.

Declaration of Interests

  1. Top of page
  2. Abstract
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Declaration of Interests
  7. References

The authors state they have no conflicts of interest to declare.


  1. Top of page
  2. Abstract
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Declaration of Interests
  7. References
  • 1
    Van Herck K, Van Damme P. Prevention of hepatitis A by Havrix: a review. Expert Rev Vaccines 2005; 4:459471.
  • 2
    Advisory Committee on Immunization Practices (ACIP), Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mortal Wkly Rep 2006; 55:123.
  • 3
    Landelijk coördinatiecentrum reizigersadvisering. National Coordination Centre for Travelers' Health Advice. National guidelines for travelers' health advice. Amsterdam: Landelijk coördinatiecentrum reizigersadvisering, 2008.
  • 4
    van Steenbergen JE, Timen A. LCI hepatitis A, May 2009. In: Beaujean DJMA, ed. LCI-guidelines infectious disease control . 2011 Edition. Bilthoven: LCI, Coordinator Infectious Disease Netherlands, 2011:218226.
  • 5
    Clemens R, Safary A, Hepburn A, et al. Clinical experience with an inactivated hepatitis A vaccine. J Infect Dis 1995; 171(Suppl 1):S44S49.
  • 6
    André F, Van Damme P, Safary A, Banatvala J. Inactivated hepatitis A vaccine: immunogenicity, efficacy, safety and review of official recommendations for use. Expert Rev Vaccines 2002; 1:923.
  • 7
    Van Herck K, Van Damme P. Inactivated hepatitis A vaccine-induced antibodies: follow-up and estimates of long-term persistence. J Med Virol 2001; 63:17.
  • 8
    Ashur Y, Adler R, Rowe M, Shouval D. Comparison of immunogenicity of two hepatitis A vaccines—VAQTA and HAVRIX—in young adults. Vaccine 1999; 17:22902296.
  • 9
    Nothdurft HD. Hepatitis A vaccines. Expert Rev Vaccines 2008; 7:535545.
  • 10
    Gelinck LB, Roukens AHE, Kroon FP, Visser LG. Praktische adviezen voor reizigers met een afweerstoornis. Ned Tijdschr Geneeskd 2008; 152:17251729.
  • 11
    Neilsen GA, Bodsworth NJ, Watts N. Response to hepatitis A vaccination in human immunodeficiency virus-infected and -uninfected homosexual men. J Infect Dis 1997; 176:10641067.
  • 12
    Launay O, Grabar S, Gordien E, et al. Immunological efficacy of a three-dose schedule of hepatitis A vaccine in HIV-infected adults: HEPAVAC study. J Acquir Immune Defic Syndr 2008; 49:272275.
  • 13
    Shire NJ, Welge JA, Sherman KE. Efficacy of inactivated hepatitis A vaccine in HIV-infected patients: a hierarchical Bayesian meta-analysis. Vaccine 2006; 24:272279.
  • 14
    van Assen S, Holvast A, Benne CA, et al. Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. Arthritis Rheum 2010; 62:7581.
  • 15
    Arad U, Tzadok S, Amir S, et al. The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis patients treated with rituximab. Vaccine 2011; 29:16431648.
  • 16
    Yri OE, Torfoss D, Hungnes O, et al. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood 2011; 118:67696771.
  • 17
    Gelinck LB, Teng YK, Rimmelzwaan GF, et al. Poor serological responses upon influenza vaccination in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis 2007; 66:14021403.
  • 18
    Gelinck LB, van der Bijl AE, Beyer WE, et al. The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination. Ann Rheum Dis 2008; 67:713716.
  • 19
    Fomin I, Caspi D, Levy V, et al. Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNF alpha blockers. Ann Rheum Dis 2006; 65:191194.
  • 20
    Kapetanovic MC, Saxne T, Nilsson JA, Geborek P. Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients. Rheumatology 2007; 46:608611.
  • 21
    Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Curr Opin Rheumatol 2008; 20:295299.
  • 22
    Kanakoudi-Tsakalidou F, Trachana M, Pratsidou-Gertsi P, et al. Influenza vaccination in children with chronic rheumatic diseases and long-term immunosuppressive therapy. Clin Exp Rheumatol 2001; 19:589594.
  • 23
    Versluis DJ, Beyer WE, Masurel N, et al. Impairment of the immune response to influenza vaccination in renal transplant recipients by cyclosporine, but not azathioprine. Transplantation 1986; 42:376379.
  • 24
    Health Council of the Netherlands. Variant Creutzfeldt-Jakob disease and blood transfusion. The Hague: Health Council of the Netherlands, 2001; publication no. 2001/02.
  • 25
    Zaaijer HL, Leentvaar-Kuijpers A, Rotman H, Lelie PN. Hepatitis A antibody titres after infection and immunization: implications for passive and active immunization. J Med Virol 1993; 40:2227.
  • 26
    D'Acremont V, Herzog C, Genton B. Immunogenicity and safety of a virosomal hepatitis A vaccine (Epaxal) in the elderly. J Travel Med 2006; 13:7883.
  • 27
    De Melker HE, van der Peet TE, Berbers GAM, et al. Seroprevalenties voor bof, mazelen, rubella, kinkhoest, Toxoplasma Gondii, Toxocara, T. spiralis en hepatitis A. Bilthoven, the Netherlands 1995. RIVM Report 213675004.
  • 28
    GlaxoSmithKline UK. Havrix Monodose Summary of Product Characteristics. Available at: (Accessed 2012 Aug 13)