LIVER TRANSPLANTATION 21:774–783, 2015
ORIGINAL ARTICLE
Serostatus Following Live Attenuated Vaccination Administered Before Pediatric Liver Transplantation Takanori Funaki,1 Kensuke Shoji,1 Ippei Miyata,1 Seisuke Sakamoto,2 Mureo Kasahara,2 Hironori Yoshii,3 Isao Miyairi,1 and Akihiko Saitoh1,4 1 Division of Infectious Diseases, Department of Medical Subspecialties, and 2Division of Transplant Surgery, Center for Transplant Surgery, National Center for Child Health and Development, Tokyo, Japan; 3 Research Foundation for Microbial Diseases of Osaka University, Kagawa, Japan; and 4Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
After liver transplantation (LT), live attenuated vaccines (LAVs) are generally contraindicated. LAVs are recommended before LT for patients 6 months of age. However, the evidence supporting this practice is limited. Patients were enrolled before and after LT. Clinical data for patients were obtained from medical records. Serum antibody titers were evaluated at the time of enrollment and prospectively. Serum antibody titers were measured with a hemagglutination inhibition test for measles and rubella and with an enzyme-linked immunosorbent assay for varicella and mumps. Univariate and multivariate analyses were performed to investigate the factors that affect the serostatus. Serological analyses of 49 patients immunized before LT (median age, 45 months; male, 35%) were performed. Underlying diseases were biliary atresia (n 5 27; 55%), metabolic diseases (n 5 13; 27%), fulminant hepatic failure (n 5 5; 10%), and others (n 5 4; 8%). The seropositivity rate after each vaccine was 46.9% (measles), 89.4% (rubella), 67.5% (varicella), and 48.8% (mumps). Factors independently associated with seronegativity were a vaccination age < 12 months for measles (P 5.002), a lower body weight for varicella (P 5 0.01), and underlying diseases other than biliary atresia for mumps (P 5.004). No serious adverse event was observed during the study period. The immunogenicity of LAVs before LT was high for rubella but low for the others. Before LT, further vaccination strategies are needed for patients. In addition, serological follow-up may be indicated for patients with factors C 2015 AASLD. associated with seronegativity. Liver Transpl 21:774-783, 2015. V Received December 11, 2014; accepted February 26, 2015. Organ transplant candidates and recipients are at higher risk for infectious complications. In this particular population, vaccine-preventable diseases such as
measles1 and varicella2 can actually be lifethreatening. For these individuals, inactivated vaccines are considered safe and are usually
Additional Supporting Information may be found in the online version of this article. Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; EU, enzyme-linked immunosorbent assay unit; HI, hemagglutination inhibition; IDSA, Infectious Diseases Society of America; IDU, interdilution unit; LAV, live attenuated vaccine; LT, liver transplantation; MMF, mycophenolate mofetil; MMR, measles, mumps, and rubella; MR, measles and rubella; NCCHD, National Center for Child Health and Development; POM, postoperative month; PSL, prednisolone; SE, standard error; SOT, solid organ transplantation; TAC, tacrolimus; WBC, white blood cell. This study was supported by a grant from the Ministry of Health, Labor, and Welfare of Japan (H25-Shinko-Ippan-009) awarded to Akihiko Saitoh. Potential conflict of interest: Nothing to report. Address reprint requests to Akihiko Saitoh, M.D., Ph.D., F.A.A.P., Department of Pediatrics, Niigata Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510 Japan. Telephone: 181-25-227-2222; FAX: 181-25-227-0778; E-mail: [email protected] DOI 10.1002/lt.24104 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases C 2015 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 21, No. 6, 2015
recommended after solid organ transplantation (SOT). Live attenuated vaccines (LAVs), on the other hand, are generally contraindicated after SOT, including liver transplantation (LT).3,4 Instead, SOT candidates are recommended to receive LAVs before transplantation.3,4 LAVs are generally administered to healthy children at 12 months of age or older because the measles, mumps, and rubella (MMR) vaccine is most effective after 12 months of age when maternal antibodies have waned. Furthermore, at that age, a child’s immune function has matured enough to respond to pathogens. For pediatric SOT candidates, however, there are limited opportunities for immunization. In some cases, LAVs have been administered as early as 6 months of age because of the timing of the transplantation.3 The recent Infectious Diseases Society of America (IDSA) guideline states that LAVs can be administered to SOT candidates at 6 to 11 months of age if they are not immunosuppressed and if the transplantation is not anticipated in the ensuing 4 weeks. In addition, repeated doses of MMR and varicella vaccines (3 months apart after the first administration of the identical vaccine) at 12 months of age are recommended if transplantation is delayed.4 According to the IDSA, another important reason to immunize patients before transplantation is that the immunity acquired from the vaccine may wane because of long-term immunosuppressive therapy after LT.5-8 Although these recommendations are reasonable, the efficacy of such a practice is unclear. Moreover, it is difficult to determine which patients would require additional follow-up. The objective of this study is to evaluate the factors associated with serostatus in LT recipients who received LAVs for MMR and varicella before LT. The focus is on patients who have undergone living donor LT. These patients usually require less immunosuppressants than those who have received cadaveric livers because of the half-matched histocompatibility between donors and recipients.9 We hypothesized that this may be an important factor in determining the seropositivity after immunization.
PATIENTS AND METHODS Patient Enrollment Patients were enrolled both before and after LT at the National Center for Child Health and Development (NCCHD), the largest pediatric LT center in Japan. The eligibility criteria for this study were (1) patients who received at least 1 LAV [a measles and rubella (MR) combination vaccine or a single-antigen vaccine licensed in Japan at the time of the study, including MMR or varicella] before LT and (2) subjects who had undergone serum antibody testing between January 2011 and June 2012. The vaccine strains were as follows: AIK-C and Schawartz-FF8 for measles; TO336, Takahashi, and Matsuura for rubella; Oka for varicella; and Hoshino and Torii for mumps.10 The exclusion criteria for this study included the follow-
FUNAKI ET AL. 775
ing: (1) patients/parents who did not consent to the study, (2) patients who could not be followed up regularly at our institution, and (3) subjects who contracted any of the 4 diseases before or during this study.
Institutional Vaccine Administration Protocol Vaccines were given to patients before transplantation according to the national immunization program in Japan11 to maximize the immunization opportunity for each patient. LAVs were administered at least 4 weeks before LT. Inactivated vaccines were administered at least 2 weeks before LT.12 The administration of LAVs is generally recommended at 1 year; however, it is acceptable to administer measles vaccine as early as 6 months of age in the event of an outbreak. Vaccines were administered either sequentially (1 by 1) or simultaneously because simultaneous vaccination was still not widely accepted in Japan during the study period.13 When LAVs were given sequentially, no specific order was set. According to the Japanese Immunization Law, there must be a 4-week period between each immunization.
Blood Sampling Blood samples were collected from the study participants. At each post-LT follow-up, an additional 2 to 3 mL of blood was collected at the outpatient clinic. The blood samples were centrifuged, and the separated plasma samples were stored at 220 C until analysis.
Immunosuppression After LT Tacrolimus (TAC) and low-dose corticosteroids were used for initial immunosuppression. TAC administration commenced on the day of LT. The target whole blood trough level of TAC was 10 to 12 ng/mL for the first 2 weeks, approximately 10 ng/mL for the following 2 weeks, and 8 to 10 ng/mL thereafter. The corticosteroid was tapered from 1.0 to 0.3 mg/kg/ day during the first month and was withdrawn within the first 3 months. Mycophenolate mofetil (MMF) was administered when patients showed TACassociated side effects or steroid-resistant refractory rejection.14
Data Collection The following characteristics of the study subjects were obtained from the medical records and analyzed: age; sex; body weight; underlying diseases; date of LT; past medical history of measles, rubella, varicella, or mumps and vaccination records; and adverse events and reactions after LAVs. Blood was collected at the time of enrollment. Subsequently, blood was collected according to the availability of the patients. Serum antibody titers for measles [hemagglutination inhibition (HI) test], rubella (HI), varicella [glycoprotein enzyme-linked immunosorbent assay (ELISA)],15 and
776 FUNAKI ET AL.
LIVER TRANSPLANTATION, June 2015
Figure 1. Changes in antibody levels for (A) measles, (B) rubella, (C) varicella, and (D) mumps vaccines in patients who enrolled in the study before LT. The first blood draw was performed before LT (without immunosuppressants), and the second blood draw was performed at a median of 6 POMs (range, 5-15 POMs). The result of “.99
6360 (1940-12,290) 2262 (495-6475) 2962 (1164-7866)
Mumps
Changes in Antibody Levels in Patients Whose Sequential Data Were Available
0.001*
.26
6230 (1940-12,290) 2659 (143-6475) 2552 (1164-7866) *Indicates statistical significance (P < 0.05).
(n 5 21)
FUNAKI ET AL. 779
vaccination (P 5 .003) were associated with seropositivity (Table 2). In addition, lesser immunosuppressants (P 5 .03), a higher serum TAC trough concentration (P 5 .001), and lower ALC (P 5 .02) were also significantly associated with seropositivity. A multivariate analysis including these significant factors demonstrated body weight at vaccination (12 months) to be an independent factor related to seropositivity (P 5 .01; Table 3).
7710 (3560-14,010) 3037 (521-7369) 3608 (1400-7866)
(n 5 26)
5420 (1940-9150) 2341 (143-4616) 2069 (1164-6680) WBC count, per lL, median (range) ANC, per lL, median (range) ALC, per lL, median (range)
(n 5 20)
Seronegative Seropositive
(n 5 13) (n 5 27)
Seropositive Seronegative
(n 5 23) Covariates
Seropositive
P Value
Varicella Measles
TABLE 2. Continued
P Value Seronegative
Mumps
P Value
LIVER TRANSPLANTATION, Vol. 21, No. 6, 2015
We further analyzed the sequential antibody data for patients whose subsequent antibody levels after LT were available. The median POMs for the first and second blood sampling after LT were as follows: MR (n 5 16), 25 and 37, respectively; varicella (n 5 15), 24 and 35, respectively; and mumps (n 5 13), 24 and 35, respectively. The seropositivity rates for each vaccine were as follows: measles, 44% (at the first blood sampling) to 56% (at the second blood sampling); rubella, 81% to 100%; varicella, 73% to 80%; and mumps, 62% to 23%. This demonstrates that high seropositivity was maintained for the rubella and varicella vaccines; in contrast, seropositivity decreased significantly for the mumps vaccine. Additionally, we further analyzed sequential antibody data for 6 patients whose antibody levels were available before and after LT. The median number of POMs for the second blood draw was 6 (range, 5-15). The changes in antibody levels before and after LT for each vaccine are shown in Fig. 1, and it demonstrates that antibody levels of the mumps vaccine tended to decrease gradually in all patients; however, the changes in antibody levels of measles, rubella, and varicella varied in each individual.
Difference in Seropositivity Rates Between Patients Who Received Vaccination at .99; Fig. 2).
Adverse Events or Reactions There were no obvious adverse reactions or events after pre-LT LAV administration except for 1 patient who developed a self-limited episode of fever 7 days after MR vaccination. In addition, no critical adverse reactions or posttransplant issues related to the administration of LAVs were recorded.
DISCUSSION We investigated the factors affecting the seropositivity of measles, rubella, varicella, and mumps vaccines given to patients before LT. Rubella vaccine administration before LT was associated with a relatively high rate of seropositivity even after LT. On the other hand, the other LAVs were suboptimal in comparison with healthy patients who demonstrated a sustained seropositivity greater than 90%.16 To our knowledge, this is the first study, consisting mainly of living donor LT recipients, that evaluated the factors associated with the seropositivity of LAVs given before LT. We found
that the independent factors associated with seropositivity in patients who received LAVs were the age at measles vaccination (12 or
ORIGINAL ARTICLE
Serostatus Following Live Attenuated Vaccination Administered Before Pediatric Liver Transplantation Takanori Funaki,1 Kensuke Shoji,1 Ippei Miyata,1 Seisuke Sakamoto,2 Mureo Kasahara,2 Hironori Yoshii,3 Isao Miyairi,1 and Akihiko Saitoh1,4 1 Division of Infectious Diseases, Department of Medical Subspecialties, and 2Division of Transplant Surgery, Center for Transplant Surgery, National Center for Child Health and Development, Tokyo, Japan; 3 Research Foundation for Microbial Diseases of Osaka University, Kagawa, Japan; and 4Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
After liver transplantation (LT), live attenuated vaccines (LAVs) are generally contraindicated. LAVs are recommended before LT for patients 6 months of age. However, the evidence supporting this practice is limited. Patients were enrolled before and after LT. Clinical data for patients were obtained from medical records. Serum antibody titers were evaluated at the time of enrollment and prospectively. Serum antibody titers were measured with a hemagglutination inhibition test for measles and rubella and with an enzyme-linked immunosorbent assay for varicella and mumps. Univariate and multivariate analyses were performed to investigate the factors that affect the serostatus. Serological analyses of 49 patients immunized before LT (median age, 45 months; male, 35%) were performed. Underlying diseases were biliary atresia (n 5 27; 55%), metabolic diseases (n 5 13; 27%), fulminant hepatic failure (n 5 5; 10%), and others (n 5 4; 8%). The seropositivity rate after each vaccine was 46.9% (measles), 89.4% (rubella), 67.5% (varicella), and 48.8% (mumps). Factors independently associated with seronegativity were a vaccination age < 12 months for measles (P 5.002), a lower body weight for varicella (P 5 0.01), and underlying diseases other than biliary atresia for mumps (P 5.004). No serious adverse event was observed during the study period. The immunogenicity of LAVs before LT was high for rubella but low for the others. Before LT, further vaccination strategies are needed for patients. In addition, serological follow-up may be indicated for patients with factors C 2015 AASLD. associated with seronegativity. Liver Transpl 21:774-783, 2015. V Received December 11, 2014; accepted February 26, 2015. Organ transplant candidates and recipients are at higher risk for infectious complications. In this particular population, vaccine-preventable diseases such as
measles1 and varicella2 can actually be lifethreatening. For these individuals, inactivated vaccines are considered safe and are usually
Additional Supporting Information may be found in the online version of this article. Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; EU, enzyme-linked immunosorbent assay unit; HI, hemagglutination inhibition; IDSA, Infectious Diseases Society of America; IDU, interdilution unit; LAV, live attenuated vaccine; LT, liver transplantation; MMF, mycophenolate mofetil; MMR, measles, mumps, and rubella; MR, measles and rubella; NCCHD, National Center for Child Health and Development; POM, postoperative month; PSL, prednisolone; SE, standard error; SOT, solid organ transplantation; TAC, tacrolimus; WBC, white blood cell. This study was supported by a grant from the Ministry of Health, Labor, and Welfare of Japan (H25-Shinko-Ippan-009) awarded to Akihiko Saitoh. Potential conflict of interest: Nothing to report. Address reprint requests to Akihiko Saitoh, M.D., Ph.D., F.A.A.P., Department of Pediatrics, Niigata Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510 Japan. Telephone: 181-25-227-2222; FAX: 181-25-227-0778; E-mail: [email protected] DOI 10.1002/lt.24104 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases C 2015 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 21, No. 6, 2015
recommended after solid organ transplantation (SOT). Live attenuated vaccines (LAVs), on the other hand, are generally contraindicated after SOT, including liver transplantation (LT).3,4 Instead, SOT candidates are recommended to receive LAVs before transplantation.3,4 LAVs are generally administered to healthy children at 12 months of age or older because the measles, mumps, and rubella (MMR) vaccine is most effective after 12 months of age when maternal antibodies have waned. Furthermore, at that age, a child’s immune function has matured enough to respond to pathogens. For pediatric SOT candidates, however, there are limited opportunities for immunization. In some cases, LAVs have been administered as early as 6 months of age because of the timing of the transplantation.3 The recent Infectious Diseases Society of America (IDSA) guideline states that LAVs can be administered to SOT candidates at 6 to 11 months of age if they are not immunosuppressed and if the transplantation is not anticipated in the ensuing 4 weeks. In addition, repeated doses of MMR and varicella vaccines (3 months apart after the first administration of the identical vaccine) at 12 months of age are recommended if transplantation is delayed.4 According to the IDSA, another important reason to immunize patients before transplantation is that the immunity acquired from the vaccine may wane because of long-term immunosuppressive therapy after LT.5-8 Although these recommendations are reasonable, the efficacy of such a practice is unclear. Moreover, it is difficult to determine which patients would require additional follow-up. The objective of this study is to evaluate the factors associated with serostatus in LT recipients who received LAVs for MMR and varicella before LT. The focus is on patients who have undergone living donor LT. These patients usually require less immunosuppressants than those who have received cadaveric livers because of the half-matched histocompatibility between donors and recipients.9 We hypothesized that this may be an important factor in determining the seropositivity after immunization.
PATIENTS AND METHODS Patient Enrollment Patients were enrolled both before and after LT at the National Center for Child Health and Development (NCCHD), the largest pediatric LT center in Japan. The eligibility criteria for this study were (1) patients who received at least 1 LAV [a measles and rubella (MR) combination vaccine or a single-antigen vaccine licensed in Japan at the time of the study, including MMR or varicella] before LT and (2) subjects who had undergone serum antibody testing between January 2011 and June 2012. The vaccine strains were as follows: AIK-C and Schawartz-FF8 for measles; TO336, Takahashi, and Matsuura for rubella; Oka for varicella; and Hoshino and Torii for mumps.10 The exclusion criteria for this study included the follow-
FUNAKI ET AL. 775
ing: (1) patients/parents who did not consent to the study, (2) patients who could not be followed up regularly at our institution, and (3) subjects who contracted any of the 4 diseases before or during this study.
Institutional Vaccine Administration Protocol Vaccines were given to patients before transplantation according to the national immunization program in Japan11 to maximize the immunization opportunity for each patient. LAVs were administered at least 4 weeks before LT. Inactivated vaccines were administered at least 2 weeks before LT.12 The administration of LAVs is generally recommended at 1 year; however, it is acceptable to administer measles vaccine as early as 6 months of age in the event of an outbreak. Vaccines were administered either sequentially (1 by 1) or simultaneously because simultaneous vaccination was still not widely accepted in Japan during the study period.13 When LAVs were given sequentially, no specific order was set. According to the Japanese Immunization Law, there must be a 4-week period between each immunization.
Blood Sampling Blood samples were collected from the study participants. At each post-LT follow-up, an additional 2 to 3 mL of blood was collected at the outpatient clinic. The blood samples were centrifuged, and the separated plasma samples were stored at 220 C until analysis.
Immunosuppression After LT Tacrolimus (TAC) and low-dose corticosteroids were used for initial immunosuppression. TAC administration commenced on the day of LT. The target whole blood trough level of TAC was 10 to 12 ng/mL for the first 2 weeks, approximately 10 ng/mL for the following 2 weeks, and 8 to 10 ng/mL thereafter. The corticosteroid was tapered from 1.0 to 0.3 mg/kg/ day during the first month and was withdrawn within the first 3 months. Mycophenolate mofetil (MMF) was administered when patients showed TACassociated side effects or steroid-resistant refractory rejection.14
Data Collection The following characteristics of the study subjects were obtained from the medical records and analyzed: age; sex; body weight; underlying diseases; date of LT; past medical history of measles, rubella, varicella, or mumps and vaccination records; and adverse events and reactions after LAVs. Blood was collected at the time of enrollment. Subsequently, blood was collected according to the availability of the patients. Serum antibody titers for measles [hemagglutination inhibition (HI) test], rubella (HI), varicella [glycoprotein enzyme-linked immunosorbent assay (ELISA)],15 and
776 FUNAKI ET AL.
LIVER TRANSPLANTATION, June 2015
Figure 1. Changes in antibody levels for (A) measles, (B) rubella, (C) varicella, and (D) mumps vaccines in patients who enrolled in the study before LT. The first blood draw was performed before LT (without immunosuppressants), and the second blood draw was performed at a median of 6 POMs (range, 5-15 POMs). The result of “.99
6360 (1940-12,290) 2262 (495-6475) 2962 (1164-7866)
Mumps
Changes in Antibody Levels in Patients Whose Sequential Data Were Available
0.001*
.26
6230 (1940-12,290) 2659 (143-6475) 2552 (1164-7866) *Indicates statistical significance (P < 0.05).
(n 5 21)
FUNAKI ET AL. 779
vaccination (P 5 .003) were associated with seropositivity (Table 2). In addition, lesser immunosuppressants (P 5 .03), a higher serum TAC trough concentration (P 5 .001), and lower ALC (P 5 .02) were also significantly associated with seropositivity. A multivariate analysis including these significant factors demonstrated body weight at vaccination (12 months) to be an independent factor related to seropositivity (P 5 .01; Table 3).
7710 (3560-14,010) 3037 (521-7369) 3608 (1400-7866)
(n 5 26)
5420 (1940-9150) 2341 (143-4616) 2069 (1164-6680) WBC count, per lL, median (range) ANC, per lL, median (range) ALC, per lL, median (range)
(n 5 20)
Seronegative Seropositive
(n 5 13) (n 5 27)
Seropositive Seronegative
(n 5 23) Covariates
Seropositive
P Value
Varicella Measles
TABLE 2. Continued
P Value Seronegative
Mumps
P Value
LIVER TRANSPLANTATION, Vol. 21, No. 6, 2015
We further analyzed the sequential antibody data for patients whose subsequent antibody levels after LT were available. The median POMs for the first and second blood sampling after LT were as follows: MR (n 5 16), 25 and 37, respectively; varicella (n 5 15), 24 and 35, respectively; and mumps (n 5 13), 24 and 35, respectively. The seropositivity rates for each vaccine were as follows: measles, 44% (at the first blood sampling) to 56% (at the second blood sampling); rubella, 81% to 100%; varicella, 73% to 80%; and mumps, 62% to 23%. This demonstrates that high seropositivity was maintained for the rubella and varicella vaccines; in contrast, seropositivity decreased significantly for the mumps vaccine. Additionally, we further analyzed sequential antibody data for 6 patients whose antibody levels were available before and after LT. The median number of POMs for the second blood draw was 6 (range, 5-15). The changes in antibody levels before and after LT for each vaccine are shown in Fig. 1, and it demonstrates that antibody levels of the mumps vaccine tended to decrease gradually in all patients; however, the changes in antibody levels of measles, rubella, and varicella varied in each individual.
Difference in Seropositivity Rates Between Patients Who Received Vaccination at .99; Fig. 2).
Adverse Events or Reactions There were no obvious adverse reactions or events after pre-LT LAV administration except for 1 patient who developed a self-limited episode of fever 7 days after MR vaccination. In addition, no critical adverse reactions or posttransplant issues related to the administration of LAVs were recorded.
DISCUSSION We investigated the factors affecting the seropositivity of measles, rubella, varicella, and mumps vaccines given to patients before LT. Rubella vaccine administration before LT was associated with a relatively high rate of seropositivity even after LT. On the other hand, the other LAVs were suboptimal in comparison with healthy patients who demonstrated a sustained seropositivity greater than 90%.16 To our knowledge, this is the first study, consisting mainly of living donor LT recipients, that evaluated the factors associated with the seropositivity of LAVs given before LT. We found
that the independent factors associated with seropositivity in patients who received LAVs were the age at measles vaccination (12 or
