Efficacy of live attenuated vaccines after two doses of intravenous immunoglobulin therapy for Kawasaki disease

doi:10.21203/rs.3.rs-1617738/v1

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Research Article

Efficacy of live attenuated vaccines after two doses of intravenous immunoglobulin therapy for Kawasaki disease

https://doi.org/10.21203/rs.3.rs-1617738/v1

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Background

It is unclear when live attenuated vaccines (LAV) should be administered to children with Kawasaki disease (KD) who have received a second dose of intravenous immunoglobulin (IVIG) after failing to respond to the initial treatment. The present study aimed to assess the efficacy of LAV after two IVIG treatments and to explore the appropriate timing of vaccination.

Methods

The present, single-arm, prospective, interventional study included KD patients who had no medical history of measles, rubella, varicella, mumps or vaccinations against these diseases and received two IVIG treatments at age 6 months or older. The subjects received vaccinations against these diseases for the first time at six or nine months after their IVIG treatment. IgG specific to each virus was measured by EIA at three months after the initial vaccination. If the results were negative, the subjects received a booster vaccination at 12 months after IVIG treatment. The primary outcome was the prevalence of positivity for antibodies after the initial and booster vaccinations.

Results

The present study enrolled 11 children, three of whom were vaccinated at six months and eight at nine months after IVIG treatment. One and two subjects who were vaccinated at six months remained negative for measles and rubella antibodies, respectively, but all those vaccinated at nine months were positive. Booster vaccination for measles and rubella led to seroconversion in all patients. At the time of their initial vaccination, all the subjects were negative for mumps antibodies, and about 30% were positive for varicella. Booster vaccinations for mumps and varicella resulted in seroconversion in 82% of the subjects.

Conclusion

These findings suggested that six months may be too short an interval after two IVIG treatment before administering measles and rubella vaccines whereas nine months may be adequate. The mumps and varicella vaccines were ineffective at either time point, but a sero-response was obtainable by administering a booster vaccination.

Clinical Trial Registration: UMIN-CTR, UMIN000007174, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000008452

Kawasaki disease

intravenous immunoglobulin therapy

measles vaccine

rubella vaccine

mumps vaccine

varicella vaccine

・Passive immunity can interfere with the efficacy of live vaccines; thus, an adequate interval must be allowed after immunoglobulin therapy before live vaccines are administered.

・Live attenuated vaccination six months after a single dose of IVIG for KD may be insufficient.

・Antibody titers become undetectable by nine months after two doses of IVIG for KD.

・Six months is too short an interval after two doses of IVIG treatment for administering measles and rubella vaccines whereas nine months may be sufficient.

・The mumps and varicella vaccines were ineffective even at nine months after two doses of IVIG treatment, but a sero-response was obtainable by administering a booster vaccination.

Passive maternal immunity and immunoglobulin administration both affect the immune response to live attenuated vaccines (LAV), such as the measles- rubella (MR), varicella, and mumps vaccines, by inhibiting LAV replication. Although the evidence of the effect of passive maternal immunity on LAV replication is well-established and the current guidelines specify an interval of 12 to 15 months before LAV administration, the appropriate interval between immunoglobulin administration and LAV administration is still unclear. [1, 2]

Kawasaki disease (KD) is a vasculitis of unknown etiology occurring predominantly in children under age 5 years. [3] Its most serious complication is the coronary artery aneurysm, which occurs in about 25% of untreated patients. [5] High-dose intransvenous immunoglobulin (IVIG) 2 g/kg is commonly used to prevent coronary artery aneurysms. [3; 6; 7] However, about 20% of patients are nonresponsive to the treatment and require multiple doses of IVIG.

There is no international consensus on the timing of LAV administration after KD. Most antibodies degrade six months after only a single dose of IVIG 1.3-2 g/kg is administered [8–10]; therefore, a six-month interval is recommended in Japan whenever immunoglobulin 2 g/kg is administered. On the other hand, the US guidelines recommend an interval of more than 11 months [11] because the results of a study demonstrated that intramuscular immunoglobulin (IMIG) 80 mg/kg in healthy Apache children inhibited a serological response to measles for five months [12], and the half-life of IgG following IVIG is estimated to be about one month [13].

Unresponsiveness to IVIG requires a second dose for a total of 4 g/kg, but the appropriate timing of LAV administration in those children is unclear. Based on the half-life of IgG [13], the one-month interval after a single IVIG dose as recommended in the current guidelines should be extended by one month to adjust for the doubled dose. It also has been reported that measles antibodies became undetectable in patients with two doses of IVIG 2 g/kg (4 g/kg in total) nine months after IVIG administration [14]. However, it is unclear whether vaccinations on this schedule can produce an immune response. Furthermore, most previous studies have focused on the measles vaccine, and the evidence, especially for varicella, is still poor. To the best of our knowledge, there are as of yet no studies comparing residual antibody titers after administration of IVIG 2g/dL and 4g/dL.

In KD patients, if the interval between IVIG treatment and LAV is too short, the vaccine can be weakened. Too long an interval, on the other hand, can increase the risk of infection. Therefore, we assessed the efficacy of administering four types of LAV at nine months post IVIG treatment, which previous studies have shown to be about the time when antibodies are degraded in children with KD who are unresponsive to their first IVIG treatment and have received IVIG 4 g/kg in total.

The present, open-label, multicenter, single-arm, interventional trial was conducted at a tertiary children’s hospital and two general hospitals in Tokyo, Japan from January 2012 through May 2015. The study was conducted in accordance with the principles of the Declaration of Helsinki and the ethical guidelines of Japan. The ethics committee at each institute approved the study.

Patient selection, data collection

The inclusion criteria were patients who 1) received IVIG for KD; 2) had no medical history of measles, rubella, varicella or mumps; 3) had no history of vaccination against these diseases; and 4) were aged 6 months to less than 5 years. The exclusion criteria were patients with 1) a hematological or oncological disease, immunodeficiency or chromosomal abnormality; 2) immunosuppressant or systemic steroid administration within one month before hospitalization for KD; and 3) chronic kidney disease. Written informed consent was obtained from the guardian of each participant. Of the subjects in previous studies on LAV in KD patients [8], only those who received two IVIG doses were included.

Study protocol

The subjects received a measles and rubella vaccination (freeze-dried live attenuated measles and rubella combined vaccine [Schwarz FF-8 strain and TO-336 strain containing more than 5,000 FFU and 1,000 FFU, respectively] from Takeda Pharmaceutical Company Ltd.), a mumps vaccination (dried live attenuated mumps vaccine [Torii strain containing more than 5,000 CCID50] from Takeda Pharmaceutical Company Ltd.), and a varicella vaccination (freeze-dried live attenuated varicella vaccine [Oka strain containing more than 1,000 PFU] from The Research Foundation for Microbial Diseases of Osaka University) nine months after IVIG treatment for KD. The combined measles-mumps-rubella vaccine is unavailable in Japan. The antibody titer for measles, mumps, rubella, and varicella was examined at three months after LAV administration using an enzyme immunoassay (EIA); if the results were negative, the subjects were vaccinated again at 12 months after their IVIG treatment (Supplemental Figure). The immunoglobulin used at Tokyo Metropolitan Children’s Medical Center was Venoglobulin® IH manufactured by Japan Blood Products Organization.

Assessment

The subjects received a laboratory test at baseline (before IVIG), two days, three months, six months, nine months, 12 months , and 15 months after IVIG treatment. The antibody titers for measles, rubella, mumps, and varicella were evaluated with reference to virus-specific IgG detected by EIA. The hemagglutination inhibition titers (HI) for measles, rubella, and mumps, Neutralizing antibody titers (NT) for measles and mumps and immune adherence agglutination (IAHA) for varicella were also performed. All the tests except EIA were performed only if serum was available. Commercially available EIA kits (Denka Seiken, Tokyo, Japan) were used to measure the antibody titer for measles, rubella, mumps, and varicella. The laboratory results were interpreted according to the manufacturer’s instructions. Seroconversion (seropositivity = responsiveness) was defined as a positive antibody titer (virus-specific IgG level ≥4.0), and unresponsiveness was defined as a borderline or negative antibody titer (virus-specific IgG level <4.0). The conversion formulas were as follows: for measles, EIA value × 45 = international value (mIU/mL) [25]; for rubella, EIA value × 2.3 = international value (IU/mL) [26]; and for varicella, EIA value × 50 = international value (mIU/mL) [27]. The antibody titer for mumps was unable to be converted to international units. A single instance of seroconversion was considered to indicate a positive response. For the other antibody tests, the cutoff points recommended in the manufacturer’s instructions or in previous studies were used. The cutoff point for the measles HI antibody titer was 1:8; for the measles NT antibody titer, 1:4; for the mumps HI antibody titer, 1:8; for the mumps NT antibody titer, 1:4; for the rubella HI antibody titer, 1:8; and for the varicella antibody IAHA titer, 1:2 [22, 23, 28].

Outcome measures and statistics

The primary outcome was the response rate to each initial vaccination and the booster vaccination for each virus as measured using the EIA. A positive response to the initial vaccination was considered sufficient proof of positivity regardless of whether a booster vaccination was given. The patient characteristics were expressed as proportions for categorical data and the mean for continuous data. To evaluate the duration until the undetectability of antibodies after IVIG, the proportion of positive antibody test results was evaluated before the initial vaccination. The efficacy of the initial and booster vaccinations at 12 and 15 months after IVIG was then assessed. Vaccine efficacy at 15 months was assessed both in the entire cohort and in the subgroup with a booster vaccination. Each EIA antibody titer was summarized in a boxplot. To assess the differences in efficacy by the timing of vaccination, the antibody titers measured by EIA at three months after the initial vaccination between groups receiving their initial vaccination at six months and nine months after IVIG treatment were compared using the unpaired t-test. All analyses were performed using SPSS ® Version 27.0 (IBM Corp, Armonk, NY, USA).

Patient characteristics

Fifty-one children with KD receiving IVIG were continuously assessed for eligibility, and seven were excluded in accordance with the exclusion criteria. Forty-five subjects who received only a single IVIG dose were excluded, and 11 subjects with two IVIG doses received the initial vaccination (Fig. 1). None of the patients contracted any of the diseases of interest during follow-up or were lost to follow-up. Three patients were mistakenly vaccinated at six months post IVIG treatment and were evaluated for the efficacy of the initial vaccination at nine months. These patients received a booster vaccination at 12 months if needed. Table 1 shows the patient characteristics.

Clinical Outcomes

Table 2 shows the percentage of antibody positivity on EIA for measles, mumps, rubella, and varicella after vaccination. The mean interval between IVIG treatment and the initial vaccination was 178 (SD 13) and 278 (SD 11) days for those vaccinated at six and nine months, respectively, and the mean interval between IVIG treatment and the booster vaccination was 378 (SD 25) days. Except for mumps, which was negative in all the subjects, the percentage of antibody positivity after vaccination was higher for those vaccinated at nine months. The interval from IVIG treatment to the booster vaccination in subjects who received their initial vaccination at six months and nine months was on average 360 (SD 15) days and 389 days (SD 24) days, respectively. Regarding the initial vaccination against measles and rubella viruses, the immune response was inadequate at 6 months post-IVIG, but seroconversion was observed in all subjects for measles and rubella at 9 months post-IVIG. Immune responses were insufficient for mumps and varicella at any vaccination timing. After the booster vaccine, all the subjects had a positive antibody titer for measles and rubella, 82% had a positive titer for mumps and varicella and 73% had a positive titer for all four vaccines.

Transition in antibody titers

Figure 2 shows the transition in the antibody titer for each vaccine on EIA before and after IVIG. The antibody titers were undetectable before IVIG but increased markedly after IVIG treatment; they were very low at three months after IVIG and became undetectable at six months. The antibody titers increased after each vaccination. Comparison of antibody titers at three months after the initial vaccination with those at six months and nine months after IVIG treatment showed that the measles antibody titer was significantly higher in patients who were vaccinated at nine months after IVIG treatment (Table 3).

Table 4 shows the change in the percentage of positive antibody tests for each virus before and after IVIG treatment. All the subjects were negative on EIA before, but became positive after, IVIG treatment. Even at three months after IVIG treatment, more than 80% of the subjects were still positive for all the antibodies except mumps.

All the subjects were negative for the antibodies on EIA at six months after IVIG treatment, but unvaccinated subjects remained negative even after nine months. Antibodies against measles on NT, antibodies against rubella on HI, and antibodies against varicella on IAHA were detectable in 10%, 60%, and 90% of the subjects, respectively, at six months. At nine months, all subjects were negative except for rubella HI and varicella IAHA. Some of the subjects receiving their initial vaccination at six months post IVIG treatment were negative for either measles or rubella antibodies, but all the subjects receiving their initial vaccination at nine months post-IVIG were positive for both antibodies. None of the subjects were positive for the mumps antibody after the initial vaccination at any time point, and 81% of the subjects were observed seroconversion on EIA after the booster vaccination. Positivity for the varicella antibody was confirmed by IAHA in 75% of the subjects at nine months after IVIG treatment. In contrast to the positivity of 38% by the initial vaccination at nine month after IVIG on EIA, all the subjects were positive for the antibodies on IAHA.

Summary

The present, prospective study evaluated the efficacy of LAV in patients with KD who received two IVIG treatments. Some subjects who received the measles and rubella vaccines at six months after their IVIG treatment were negative for antibodies to these vaccines, but all the subjects who received the vaccines at nine months were positive for the antibodies. The subjects who received the mumps and varicella vaccines at both six and nine months post-IVIG showed a poor response, but a booster vaccination resulted positivity in 80% of the subjects. Antibody titers were negative on both EIA assays at six months post-IVIG but remained positive for measles on NT, for rubella on HI, and for VZ on IAHA. To the best of our knowledge, the present study is the first to evaluate changes in the titer of antibodies against four viruses and their direct effect on patients with KD receiving two IVIG doses (4 mg/kg).

Efficacy of LAV in KD patients with two IVIG doses

The present study found that the optimal timing for the measles and rubella vaccines might be nine months post-IVIG; the mumps and varicella vaccines, however, were ineffective at either timing. A previous study assessing the efficacy of LAV in patients with KD with only a single IVIG dose (2 g/kg) reported a suboptimal effect of vaccination at six months post-IVIG [8]. Further, a retrospective study concluded that vaccination at nine months post-IVIG was preferable. [15] However, in terms of the timing of LAV administration post-IVIG, the Advisory Committee on Immunization Practices recommends an interval of 11 months for IVIG 2 g/kg [16] and 12 months for 4 g/kg based on the estimated half-life of immunoglobulin of one month. The present study found that where the measles and rubella vaccines were concerned, the results contradicted the guideline recommendations, which extrapolated intervals based on the half-life of immunoglobulin and the fact that the response to the measles vaccine was inhibited for five months after administration of a 80 mg/kg intramuscular dose to healthy children [12], indicating that a shorter interval post-IVIG may be better. Moreover, our findings suggested that the measles and rubella vaccines can be given at similar intervals post-IVIG even if the IVIG dose were to be increased from 2 to 4 g/kg. On the other hand, vaccination at six months post-IVIG led to a significantly lower measles antibody titer than vaccination at nine months, suggesting that the six-month interval between the IVIG treatments and vaccination is too short. The poor efficacy of the mumps and varicella vaccines may have been caused by the amount of specific antibodies in the immunoglobulin, the method used to measure antibody titers, and the vaccine strain. Since the immunoglobulin was obtained from blood donors, their immune characteristics could have affected the results. [8] Furthermore, some concerns have been raised about the efficacy of the Torii strain of the mumps vaccine. [17]

In subjects who were negative for the antibodies after their initial vaccination, after a booster vaccination all became positive for measles and rubella antibodies, and 80% became positive for mumps and varicella antibodies. These results were similar to those of previous studies evaluating the efficacy of booster vaccinations in non-responders to the initial measles, mumps, and rubella vaccination after a single-dose IVIG treatment. [8; 18] This similarity may be explained by the degradation of the residual antibodies, the effectiveness of the booster vaccination or both.[8] Vaccine efficacy may be inhibited for a certain period of time even after the antibody titer of each virus falls below detectable levels. Maternal antibodies are undetectable in most infants during the first six months of life, [19] and the response to LAV is suboptimal until after age 1 year. [20] The varicella and mumps vaccines were ineffective at nine months post-IVIG, and seroconversion occurred mainly after a booster vaccination, emphasizing the importance of booster vaccinations in KD patients as in generally healthy children. [21]

Changes in antibody titer

In the present study, antibodies against each virus were undetectable on EIA at six months post-IVIG. Antibodies against Measles on NT and rubella on HI were detectable in 10% and 60% of the subjects, respectively, at six months, and varicella antibodies were detectable at nine months on IAHA in 75% of the subjects. A previous report of changes in measles antibody titers on EIA and NT in KD patients after two IVIG treatments demonstrated that a residual titer was detectable at six months but was undetectable at nine months. [14] The results of the present study were in line with these findings. In previous reports investigating changes in antibody titers after a single IVIG dose, antibodies were detectable at five months in patients receiving on average IVIG 1.3 g/kg [9], and the titer at six months in patients receiving on average 2 g/kg was 9% and 33% on NT and EIA for measles, respectively; 48% for rubella HI; and 6% and 96% for varicella on EIA and IAHA, respectively. [8] Comparison of the results of the present study with those of a previous study evaluating changes in the titer of antibodies against the four viruses on EIA after a single IVIG dose [8] demonstrated a significantly higher residual antibody titer in the two IVIG-dose group for all the viruses on day 2. However, after three months the titers did not differ significantly between the two groups (Supplemental table 1). In KD patients, increased vascular permeability causes protein leakage and decreased serum protein levels [22], and serum IgG in these patients has been shown to correlate inversely with fever duration. [23] The residual antibodies may become undetectable more quickly, especially in severe KD patients unresponsive to IVIG who have received two IVIG doses. [14] The findings of the present study support these observations.

Based on the trends in the antibody titers in this study, especially after vaccination, it may be advisable to administer the measles and rubella vaccines to children with KD with two IVIG doses at nine months post-IVIG. On the other hand, for varicella and mumps, vaccination at nine months post-IVIG may be insufficient. The timing of vaccination should be adjusted by the prevalence of the disease in a given region. In areas where the frequency of epidemics is high, early vaccination may be considered, but if the vaccine is administered early, its efficacy should be evaluated serologically on a later date. If the sero-response is found to be inadequate, a booster vaccination should be administered.

Limitations

The present study has several limitations. First, the patient pool was too small for any definitive conclusions to be drawn. Second, because there was no control group of healthy subjects, imprecisions in the assessment of vaccine efficacy were unable to be eliminated. Third, this study included only Japanese subjects receiving vaccinations under the Japanese health care system; thus, the results may not be generalizable to other regions or vaccine strains.

The LAV seroconversion rates were low for measles and rubella at six months after two IVIG doses for KD but adequate at nine months. The mumps and varicella vaccines were ineffective at either timing, but a sero-response was achieved by a booster vaccination. While the measles and rubella vaccines should be administered at nine months post-IVIG, the results of our study indicated that only one vaccination may be insufficient, especially for mumps and varicella. A future study including a larger number of children who have received two doses of IVIG may help determine the optimal timing for LAV including both the initial and booster vaccinations.

Intravenous immunoglobulin therapy, IVIG; Kawasaki disease, KD; live attenuated vaccine, LAV; standard deviation, SD.

Competing interests:

Masaru Miura received honoraria from the Japan Blood Products Organization, Teijin Pharma Limited, Nihon Pharmaceutical, and Mitsubishi Tanabe Pharma Corporation which were unrelated to the submitted work. The other authors have no conflicts of interest to disclose.

ACKNOWLEDGEMENTS

The authors would like to thank Dr. Yuho Horikoshi of the Division of Infectious Diseases, Department of Pediatrics at Tokyo Metropolitan Children's Medical Center for his support; Ms. Makiko Yoshida, Ms. Yuriko Ozaki, and the staff at the Clinical Research Support Center of Tokyo Metropolitan Children’s Medical Center for their help with data management; Mr. Takashi Nakamoto and Ms. Masako Tomotsune for their assistance with data collection; and Mr. James Robert Valera for his assistance in reviewing and editing this manuscript. The authors would like to express their deep appreciation to all the participants and their parents and all the staff at the participating institutions.

Funding Source: This work was supported by the Tokyo Metropolitan Government and Japan Kawasaki Disease Research Center.

Author Contributions:

YM conceptualized and designed the study, performed the statistical analysis, and drafted and revised the initial manuscript. HS coordinated the study, supervised the data collection, and revised manuscript.

MM helped to conceptualize and design the study, interpret the data, and review and revise the manuscript.

All the authors approved the final version of the manuscript as submitted and agree to be accountable for all aspects of the work.

Availability of data and material

Data sharing statement: visual participant data will not be made available.

Ethics approval

The ethics committee at each institute approved the study.

Consent to participate

Written informed consent was obtained from the subjects’ parents.

Consent for publication

Written informed consent was obtained from the subjects’ parents.

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Table 1. Patient characteristics

Variables
Patients, n	11
Sex, female, n (%)	3 (27)
Age (month) at IVIG, mean (SD)	11.7 (0.9)
Gestational age (week), mean (SD)	39.3 (0.3)
Birth weight (kg), mean (SD)	3.1 (0.09)
Weight at IVIG (kg), mean (SD)	8.7 (0.3)
Height at IVIG (cm), mean (SD)	73.5 (1.3)
IVIG/ body weight (g/kg), mean (SD)	1.9 (0.1)
WBC (/µL), mean (SD)	11,956 (1,296)
Platelets (x10⁴/µL), mean (SD)	31.8 (2.2)
AST (IU/L), mean (SD)	125.3 (40.6)
Na (mEq/L), mean (SD)	134.9 (0.7)
CRP (mg/dL), mean (SD)	5.1 (0.8)
IgG (mg/dL), mean (SD)	505.8 (42.9)
Abbreviations
IVIG, intravenous immunoglobulin; WBC, white blood cell; AST, aspartate aminotransferase; CRP, C-reactive protein; SD, standard deviation

Table 2. Seroconversion after initial and booster vaccinations per vaccine

Condition	Initial vaccination post-IVIG		p-value	Booster vaccination post-IVIG ‡
Condition	6 months	9 months	p-value	12 months
Whole †	0/3 (0, 0-71)	0/8 (0, 0-37)	-	8/11 (73, 39-94)
Measles	2/3 (67, 9-99)	8/8 (100, 63-100)	0.27	11/11 (100, 72-100)
Mumps	0/3 (0, 0-71)	0/8 (0, 0-37)	-	9/11 (82, 48-98)
Rubella	1/3 (33, 1-91)	8/8 (100, 63-100)	0.06	11/11 (100, 72-100)
Varicella	1/3 (33, 1-91)	3/8 (38, 9-76)	1	9/11 (82, 48-98)

Data are expressed as the number of responders / number inoculated (%, 95% confidence interval)

† Complete response to measles, mumps, rubella, and varicella-zoster vaccines

‡ Results of the initial vaccination were applied to patients without a booster vaccination.

Table 3. Comparison of post-vaccination antibody titers between vaccination at 6 months and vaccination at 9 months post-IVIG treatment

	Initial vaccination timing	n	mean (SD)	p-value
Measles	6 months	3	585 (681)	0.02
Measles	9 months	8	2400 (947)	0.02
Rubella	6 months	3	18 (32)	0.05
Rubella	9 months	8	152 (97)	0.05
Mumps	6 months	3	1 (2)	0.70
Mumps	9 months	8	2 (2)	0.70
Varicella	6 months	3	115 (103)	0.95
Varicella	9 months	8	110 (122)	0.95

Abbreviation: n, number; SD, standard deviation.

Table 4. Transition in titers for four viruses in patients with KD after two IVIG doses

		Pre-IVIG	Day 2	Month 3	Month 6	Month 9		Month 12	Month 15
		Pre-IVIG	Day 2	Month 3	Month 6	No vaccination	Initial vaccination at Month 6	Initial vaccination at Month 9	Whole	Booster vaccination
Measles	EIA	0 (0/11)	100 (10/10)	91 (10/11)	0 (0/10)	0 (0/8)	67 (2/3)	100 (8/8)	100 (11/11)	100 (2/2)
	HI	0 (0/10)	100 (11/11)	36 (4/11)	0 (0/10)	0 (0/8)	67 (2/3)	100 (7/7)	100 (11/11)	100 (2/2)
	NT	0 (0/6)	67 (2/3)	10 (1/10)	10 (1/10)	0 (0/8)	67 (2/3)	100 (7/7)	100 (11/11)	100 (2/2)
Mumps	EIA	0 (0/11)	100 (10/10)	0 (0/11)	0 (0/10)	0 (0/8)	0 (0/3)	0 (0/8)	81 (9/11)	81 (9/11)
	HI	0 (0/11)	100 (10/10)	0 (0/11)	0 (0/10)	0 (0/8)	0 (0/3)	0 (0/7)	30 (3/10)	30 (3/10)
	NT	0 (0/5)	0 (0/3)	0 (0/10)	0 (0/10)	0 (0/8)	0 (0/3)	0 (0/7)	10 (1/10)	10 (1/10)
Rubella	EIA	0 (0/11)	100 (10/10)	82 (9/11)	0 (0/10)	13 (1/8)	33 (1/3)	100 (8/8)	100 (11/11)	100 (2/2)
Rubella	HI	9 (1/11)	100 (10/10)	100 (11/11)	60 (6/10)	13 (1/8)	67 (2/3)	100 (7/7)	100 (11/11)	100 (2/2)
Varicella	EIA	0 (0/11)	100 (10/10)	82 (9/11)	0 (0/10)	0 (0/8)	33 (1/3)	38 (3/8)	64 (7/11)	71 (5/7)
Varicella	IAHA	40 (2/5)	67 (2/3)	100 (10/10)	90 (9/10)	75 (6/8)	100 (3/3)	100 (7/7)	100 (10/10)	100 (7/7)

Data are expressed as % (no. responders/no. inoculated)

Abbreviations: IVIG, intravenous immunoglobulin; EIA, enzyme immunoassay; HI, hemagglutination inhibition; NT, neutralization test; IAHA, immune adherence hemagglutination.

Competing interest reported. Masaru Miura received honoraria from the Japan Blood Products Organization, Teijin Pharma Limited, Nihon Pharmaceutical, and Mitsubishi Tanabe Pharma Corporation which were unrelated to the submitted work. The other authors have no conflicts of interest to disclose.

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Efficacy of live attenuated vaccines after two doses of intravenous immunoglobulin therapy for Kawasaki disease

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Abstract

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What Is Known

What Is New

Introduction

Materials And Methods

Results

Patient characteristics

Clinical Outcomes

Transition in antibody titers

Discussion

Summary

Efficacy of LAV in KD patients with two IVIG doses

Changes in antibody titer

Limitations

Conclusion

Abbreviations

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