Antibody Responses in Hematopoietic Cell Transplantation Recipients after Vaccination Against Haemophilus Influenzae Type b and Streptococcus pneumoniae

Yae-Jean Kim; Ji-Young Hwang; Soo-Han Choi; Eunhye Kong; Yanghyun Kim; Ki-Sup Park; Keon-Hee Yoo; Ki-Woong Sung; Hong Hoe Koo; Kyung-Hyo Kim

doi:10.14776/kjpid.2014.21.2.81

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Kim, Hwang, Choi, Kong, Kim, Park, Yoo, Sung, Koo, and Kim: Antibody Responses in Hematopoietic Cell Transplantation Recipients after Vaccination Against Haemophilus Influenzae Type b and Streptococcus pneumoniae

Original Article

Korean J Pediatr Infect Dis 2014;21(2):81-95.

Published online: 20 January 2014

DOI: https://doi.org/10.14776/kjpid.2014.21.2.81

Antibody Responses in Hematopoietic Cell Transplantation Recipients after Vaccination Against Haemophilus Influenzae Type b and Streptococcus pneumoniae

Yae-Jean Kim, M.D.^∗, Ji-Young Hwang, PhD.^†, Soo-Han Choi, M.D.^†,^‡, Eunhye Kong, R.N.^†, Yanghyun Kim, R.N., Ki-Sup Park, M.S.^†, Keon-Hee Yoo, M.D.^∗, Ki-Woong Sung, M.D.^∗, Hong Hoe Koo, M.D.^∗, Kyung-Hyo Kim, M.D.^∫,^∥

^∗Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

^†Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

^‡Department of Pediatrics, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea

^∫Department of Pediatrics, School of Medicine, Ewha Womans University, Seoul, Korea

^∥Center for Vaccine Evaluation and Study, School of Medicine, Ewha Womans University, Seoul, Korea

Correspondence: Kyung-Hyo Kim, M.D. Department of Pediatrics, Ewha Womans University School of Medicine, Korea Tel: +82-02-2650-2857, Fax:+82-2-2650-2817 E-mail: kaykim@ewah.ac.kr

Received 10 June 2014 Revised 2 May 2014 Accepted 5 May 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Hematopoietic cell transplantation (HCT) recipients are vulnerable to invasive infection by Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (Sp). This study was performed to evaluate immune responses after Hib and Sp vaccination in Korean pediatric HCT recipients. Methods: Patients were prospectively enrolled at Samsung Medical Center during 2009–2011. ELISA tests to detect anti- PRP IgG antibody and antibodies to Sp serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F were performed at the Center for Vaccine Evaluation and Study, Ewha Medical Research Institute. Results: Ten patients (two allogeneic, eight autologous recipients) with median age 5.4 years (range 2.7–12.2 years) were enrolled. Before Hib vaccination, 60% of patients' anti-PRP IgG titers were below 0.15 μ g/mL. After vaccination, 100% of patients' anti-PRP IgG titers increased above 0.15 μ g/mL (cut-off value for detection) and 1.0 μ g/mL (cut-off value for seroprotection). For pneumococcus, in 2–5 year-old patients, pre-vaccination geometric mean concentrations (GMCs) of IgG for six serotypes (4, 6B, 9V, 14, 18C, and 23F) were below 0.35 μ g/mL and at 5 months post-vaccination GMCs of IgG for all seven serotypes increased to above 0.35 μ g/mL. In patients older than 5 years, pre-vaccination GMCs of IgG for four serotypes (4, 9V, 14, and 23F) were below 0.35 μ g/mL and at 3 months post-vaccination GMCs of IgG for all seven serotypes increased to above 0.35 μ g/mL. Conclusion: Most HCT recipients had low or no protective antibodies to Hib and Sp before vaccination, but showed good immune responses to protective levels after vaccination.

Keywords: Stem cell transplant, vaccination, Hib, Pneumococcus

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Fig. 1.

Lymphocyte proliferation test of enrolled patients before vaccination. Patients' lymphocyte proliferation activity was measured by stimulating lymphocytes in vitro with PHA and ConA, and SI was calculated by comparing the value to normal controls. Each line shows changes in SI values according to the concen-tration of PHA and ConA. Black dotted lines represent the median SI values of lymphocytes from immunocompetent normal control individuals. PHA, phytohe-magglutinin; ConA, concanavalin A; SI, stimulation index.

Fig. 2.

Anti-PRP IgG concentrations after Hib vaccination. Hib vaccination was performed at months 0, 2, and 12, and blood draws for serological tests were performed at months 0, 3, and 13. The third Hib vaccination was not performed in patient 6 and 7.

Fig. 3.

Antibody response for S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F in group I (A) and group II (B) A. In group I, antibodies were measured after two doses of PCV7 and one dose of PPSV 23 in patients 2–5 years of age. Patients were vaccinated with PCV7 at months 0 and 2, and with PPSV23 at month 4. Blood was drawn for serological testing at months 0, 3, 5 and 13. B. In group II, antibodies were measured after one dose of PPSV23 at month 0 and blood was drawn for serological tests at months 0, 1, 3, and 13. GMC, geometric concentration; PCV7, pneumococcal conjugate vaccine 7-valent; PPSV23, pneumococcal polysaccharide vaccine 23-valent; Pre, prevaccination.

Table 1.

Schedule for Vaccination and Serum Collection

	Month	0	1	2	3	4	5	6	12	13
Group I	Hib	↓		↓					↓
2–5 years	PCV7	↓		↓
	PPSV23					↓
	Serum collection	↓			↓		↓			↓
Group II	Hib	↓		↓					↓
>5 years	PPSV23	↓
	Serum collection	↓	↓		↓					↓
All patients	s HepB	↓		↓					↓
	DTaP or Td	↓		↓					↓
	IPV	↓		↓					↓
	HepA	↓						↓

Abbreviations: Hib, Haemophilus influenzae type b; PCV7, 7-valent pneumococcal conjugate vaccine; PPSV23, 23-valent pneu-mococcal polysaccharide vaccine; HepB, hepatitis B vaccine; DTaP, diphteria-tetanus-acellular pertussis vaccine; Td, tetanus- diphteria vaccine; IPV, inactivated polio vaccine; HepA, hepatitis A vaccine; MMR, measles-mumps-rubella vaccine was given to patients when at least 2 years have passed after last HCT and the patient was off from immunosuppressive agent or intravenous immunoglobulin for at least one year more.

Table 2.

Patient Characteristics

Patient ID	Diagnosis	HCT type	Type of stem cells	Age at vaccination (years)	Months from last HCT to vaccination start (months)	No of HCT performed
1	Anaplastic	Auto	PBSC	2.7	13	2
	ependymoma
2	NBL	Auto	PBSC	3.0	13	2
3	NBL	Auto	PBSC	3.3	13	2
4	AML	Allo	Unrelated PBSC	3.7	16	1
5	NBL	Auto	PBSC	7.5	54	2
6	NBL	Auto	PBSC	5.6	13	2
7	NBL	Auto	PBSC	5.4	13	2
8	MBL	Auto	PBSC	11.0	14	3
9	AML	Allo	Unrelated BM (1)	12.2	52	3
			Haplo PBSC (2)
			Mismatched unrelated BM (3)
10	NBL	Auto	PBSC	5.5	15	2

Abbreviations: ID, identification; HCT, hematopoietic cell transplantation; Auto, autologous; Allo, allogeneic; NBL, neurobla stoma; AML, acute myelogenous leukemia; MBL, medulloblastoma; PBSC, peripheral blood stem cell; BM bone marrow; haplo haploidentical.

Table 3.

Lymphocyte Subsets before Vaccination

Patient ID	ALC	CD3		CD4		CD8		CD4/ CD8	CD19		CD16+56+3- (NK)		CD16+56+3+ (NKT)
Patient ID	Count (/μ L)	Count (/μL)	%	Count (/μL)	%	Count (/μL)	%	CD4/ CD8	Count (/μL)	%	Count (/μL)	%	Count (/μL)	%
1	3,414	2,102	62	1,157	34	926	27	1.25	733	21	501	15	77	2
2	3,710	1,919	62	801	26	1,048	34	0.76	462	15	555	18	92	3
3	3,706	1,279	35	889	24	815	22	1.09	1,779	48	482	13	408	11
4	2,738	1,417	52	904	33	466	17	1.94	794	29	383	14	27	1
6	4,394	1,714	39	747	17	967	22	0.77	1,626	37	791	18	44	1
7	2,910	2,273	79	1,455	50	758	26	1.92	424	15	152	5	61	2
8	2,289	704	31	389	17	320	14	1.21	1,236	54	252	11	23	1
9	3,625	2,030	56	690	19	1,230	34	0.56	690	19	830	23	–	–
10	2,098	1,059	51	399	19	608	29	0.66	860	41	147	7	0	0
Median	3,414	1,714	52	801	24	815	26	0.93	794	29	482	14	53	1.5

Abbreviations: ID, identification; ALC, absolute lymphocyte counts; Patient 5 was not tested.

Table 4.

Immunoglobulin Values before Vaccination

Patient ID	IgG (mg/dL)	IgA (mg/dL)	IgM (mg/dL)	IgD (mg/dL)	IgE (IU/mL)
1	408	8	82	0.41	15
2	1,221	25	73	0.41	3.3
3	585	23	120	0.41	2.8
4	656	53	98	0.41	1.5
6	959	85	154	13.4	37.5
7	833	65	143	1.7	5.5
8	701	77	101	0.75	130
9	994	78	157	5.98	903.3
10	505	53	57	0.41	1.5
GMC	722.64	42.25	103.82	1.02	12.52

Abbreviations: ID, identification; Ig, immunoglobulin; GMC, geometric mean concentration. Patient 5 was not tested.

Table 5.

Reported Adverse Events of Grade III or more after Vaccination

	Group I (n=16)∗		Group II (n=16)^†		Total (n=32)
	Case	%	Case	%	Case	%
Redness	0	0.0	1	6.25	1	3.1
Pain	0	0.0	1	6.25	1	3.1
Swelling	0	0.0	0	0.0	0	0.0
Induration	0	0.0	0	0.0	0	0.0
Fever (≥39.5℃)	0	0.0	0	0.0	0	0.0
Lethargy	0	0.0	0	0.0	0	0.0
Allergic reaction	0	0.0	1	6.25	1	3.1
Rash	0	0.0	1	6.25	1	3.1
Muscle pain	0	0.0	0	0.0	0	0.0
Joint pain	0	0.0	0	0.0	0	0.0
Summary	0	0.0	4	25.0	4	12.5

^∗ Four patients and four vaccination visits per patients.

^† Six patients and three vaccination visits per patients. Patient 6 and 7 didn't receive the third vaccination.

Table 6.

Anti-PRP IgG Concentration after Haemophilus influenzae Type b Vaccination

Patient ID	Anti-PRP IgG concentration (mg/mL)
Patient ID	Pre-vaccination (month 0)	One month after 2 ^nd dose (month 3)	One month after 3 ^rd dose (month 13)
1	0.08	81.57	151.29
2	0.08	0.20	36.74
3	0.08	112.84	310.47
4	2.85	33.49	206.37
5	0.08	144.66	715.35
6	0.08	19.42	ND
7	1.40	74.00	ND
8	0.08	3.55	54.84
9	1.02	3.27	33.70
10	3.69	4.35	7.99
GMC (95% CI)	0.29∗^, ^† (0.09–0.96)	15.17^∗ ^† (3.37–68.43)	88.50^† (26.38–296.80)

Abbreviations: ID, identification; Hib, Haemophilus influenzae type b; GMC, geometric mean concentration; CI, confidence interval; ND, not determined. A value of 0.08 mg/mL indicates below detection level (0.15 mg/mL).

^∗ P=0.002 by Wilcoxon matched-pairs signed-ranks test;

^† P<0.001 by nonparametric repeated measures ANOVA test.

Table 7.

Antibody Response after Two Doses of 7-valent Pneumococcal Conjugate Vaccine and One Dose of 23-valent Pneumococcal Polysaccharide Vaccine in Patients Aged 2–5 Years (Group I)

Serotype	GMC of IgG (mg/mL) (95% CI)
Serotype	Pre-vaccination (month 0) n=4	1 month after 2 ^nd PCV7 (month 3) n=4	1 month after PPSV 23 (month 5) n=4	6 months after PPSV 23 (month 13) n=4
4	0.03 (0.01–0.12)	12.38 (5.48–27.94)	7.26 (3.25–16.22)	2.32 (0.11–48.64)
6B	0.21 (0.06–0.77)	10.57 (1.38–81.21)	8.08 (1.30–50.06)	3.41 (0.06–184.40)
9V	0.14 (0.05–0.39)	10.05 (1.27–79.54)	8.20 (0.72–93.22)	2.73 (0.12–61.51)
14	0.03 (0.001–1.38)	22.78 (8.43–61.54)	22.47 (9.71–52.03)	7.12 (1.39–36.54)
18C	0.25 (0.04–1.69)	7.37 (0.75–72.26)	5.57 (0.51–61.14)	2.15 (0.04–128.4)
19F	1.14 (0.63–2.04)	12.31 (2.02–74.88)	8.89 (1.14–69.03)	2.94 (0.15–55.98)
23F	0.05 (0.01–0.22)	6.63 (0.25–178.90)	4.54 (0.26–78.52)	1.95 (0.01–339.6)

Abbreviations: GMC, geometric mean concentration; CI, confidence interval.

Table 8.

Antibody Response after One Dose of 23-valent Pneumococcal Polysaccharide Vaccine in Patients Aged >5 Years (Group II)

Serotype	GMC of IgG (mg/mL) (95% CI)
Serotype	Pre-vaccination (month 0) n=6	1 month after PPSV 23(month 1) n=2	3 months after PPSV 23 (month 3) n=6	13 months after PPSV 23 (month 13) n=4
4	0.09 (0.04–0.21)	0.61^∗∗	0.63 (0.17–2.36)	0.23 (0.03–2.04)
6B	0.59 (0.13–2.74)	0.53 (0.001–234.00)	2.17 (0.25–19.10)	0.80 (0.09–7.41)
9V	0.16 (0.05–0.47)	0.49 (0.01–36.66)	0.56 (0.14–2.25)	0.31 (0.10–0.96)
14	0.27 (0.08–0.97)	0.51 (0.35–0.74)	0.74 (0.12–4.42)	0.68 (0.02–28.17)
18C	0.48 (0.11–2.16)	0.22 (0.12–0.39)	0.94 (0.15–6.08)	0.43 (0.04–4.42)
19F	1.07 (0.32–3.64)	1.48 (0.03–78.88)	2.47 (0.68–8.95)	1.60 (0.23–10.97)
23F	0.24 (0.08–0.68)	0.12^†	0.37 (0.03–4.22)	0.15 (0.03–0.95)

95% CI ∗(1.98e–010 to 1.90e+009),

^† (2.29e–006 to 6704)

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