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The response to Typhi Vi vaccination is compromised in individuals with primary immunodeficiency

Authors:
Jeevani Kumarage at North West Anglia NHS foundation trust
Jeevani Kumarage
  • North West Anglia NHS foundation trust
Prof Suranjith L Seneviratne at Royal Free London NHS Foundation Trust
Prof Suranjith L Seneviratne
Vijitha Senaratne
Vijitha Senaratne
Vijitha Senaratne
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Amitha Fernando at Central Chest Clinic Colombo Sri Lanka
Amitha Fernando
  • Central Chest Clinic Colombo Sri Lanka
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Abstract and Figures

Measurement of an individuals ability to respond to polysaccharide antigens is a crucial test to determine adaptive immunity. Currently the response to Pneumovax® is utilized but with the success of Prevnar®, measurement of the response to Pneumovax may be challenging. The aim of the study was to assess the response to Typhi Vi vaccination in both children and adult control groups and patients with primary immunodeficiency (PID). In the control groups, >95% of the individuals had pre Typhi Vi vaccination concentrations <100 U/mL and there was significant increase in concentration post Typhi Vi vaccination (p<0.0001) with>94% achieving ≥3 fold increase in concentration (FI). The response to Typhi Vi vaccination was significantly lower in both children (p = 0.006) and adult (p = 0.002) PID groups when compared to their control groups. 11% and 55% of the children and adult PID groups respectively did not obtain a response >3FI. There were no significant differences between the responses obtained in the children and adult PID groups. When all individuals with PID were separated into those with either hypogammaglobulinemia (HYPO) or common variable immunodeficiency (CVID), both groups had a significantly lower median FI than the control group (19, 95%CI 5–56 vs 59, 95%CI 7–237; p = 0.01 and 1, 95%CI 1–56 vs 32, 95%CI 5–136; p = 0.005). Further, a >3FI differentiated the antibody responses between both the CVID and HYPO groups and their control groups (AUC: 0.83, 95%CI: 0.65–1.00, p = 0.005 and 0.81, 95% CI: 0.65–0.97, p = 0.01). The data suggests that measurement of the response to Typhi Vi vaccination could represent a complementary assay for the assessment of the response to a polysaccharide vaccine.
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The response to Typhi Vi
vaccination is compromised in
individuals with primary
immunodeficiency
Jeevani Kumarage
a
, Suranjith L. Seneviratne
b,c
, Vijitha Senaratne
d
,
Amitha Fernando
e
, Kirthi Gunasekera
e
, Bandu Gunasena
d
, Padmalal Gurugama
f
,
Sudath Peiris
g
, Antony R. Parker
h,
*, Stephen Harding
h
, Nilhan Rajiva de Silva
a
a
Department of Immunology, Medical Research Institute, Colombo 8, Sri Lanka
b
Institute of Immunity and Transplantation, Royal Free Hospital, London, UK
c
Department of Surgery, Faculty of Medicine, University of Colombo, Sri Lanka
d
National Hospital for Respiratory Diseases, Walisara, Sri Lanka
e
National Hospital of Sri Lanka/Central Chest Clinic, Colombo, Sri Lanka
f
Department of Clinical Biochemistry and Immunology, Cambridge University Hospitals NHS Foundation Trust, Hills
road, Cambridge, UK
g
Epidemiology Unit, Ministry of Health, Sri Lanka
h
The Binding Site Group Limited, 8 Calthorpe Road, Edgbaston, Birmingham, B15 1QT, UK
* Corresponding author.
E-mail address: Antony.Parker@Bindingsite.co.uk (A.R. Parker).
Abstract
Measurement of an individuals ability to respond to polysaccharide antigens is a
crucial test to determine adaptive immunity. Currently the response to
Pneumovax
®
is utilized but with the success of Prevnar
®
, measurement of the
response to Pneumovax may be challenging. The aim of the study was to assess the
response to Typhi Vi vaccination in both children and adult control groups and
patients with primary immunodeficiency (PID). In the control groups, >95% of the
individuals had pre Typhi Vi vaccination concentrations <100 U/mL and there was
significant increase in concentration post Typhi Vi vaccination (p<0.0001)
with>94% achieving ≥3 fold increase in concentration (FI). The response to Typhi
Vi vaccination was significantly lower in both children (p= 0.006) and adult
Received:
21 April 2017
Revised:
26 May 2017
Accepted:
16 June 2017
Cite as: Jeevani Kumarage,
Suranjith L. Seneviratne,
Vijitha Senaratne,
Amitha Fernando,
Kirthi Gunasekera,
Bandu Gunasena,
Padmalal Gurugama,
Sudath Peiris,
Antony R. Parker,
Stephen Harding,
Nilhan Rajiva de Silva. The
response to Typhi Vi
vaccination is compromised in
individuals with primary
immunodeficiency.
Heliyon 3 (2017) e00333.
doi: 10.1016/j.heliyon.2017.
e00333
http://dx.doi.org/10.1016/j.heliyon.2017.e00333
2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
(p= 0.002) PID groups when compared to their control groups. 11% and 55% of
the children and adult PID groups respectively did not obtain a response >3FI.
There were no significant differences between the responses obtained in the
children and adult PID groups. When all individuals with PID were separated into
those with either hypogammaglobulinemia (HYPO) or common variable
immunodeficiency (CVID), both groups had a significantly lower median FI than
the control group (19, 95%CI 5–56 vs 59, 95%CI 7–237; p= 0.01 and 1, 95%CI
1–56 vs 32, 95%CI 5–136; p= 0.005). Further, a >3FI differentiated the antibody
responses between both the CVID and HYPO groups and their control groups
(AUC: 0.83, 95%CI: 0.65–1.00, p= 0.005 and 0.81, 95% CI: 0.65–0.97, p= 0.01).
The data suggests that measurement of the response to Typhi Vi vaccination could
represent a complementary assay for the assessment of the response to a
polysaccharide vaccine.
Keywords: Health sciences, Biological sciences, Infectious disease, Vaccines,
Immunology, Medicine, Pediatrics
1. Introduction
Defective production of specific antibodies in response to polysaccharide antigens
is a major risk for infection and other complications in patients with antibody
deficiencies. Currently, specific antibody responses to Pneumovax are measured in
individuals with symptoms suggestive of a deficiency of antibody production [1].
Interpretation of the response to pneumococcal vaccination is becoming more
challenging. High pneumococcal pre-immunization levels in the general population
may limit the response to vaccination [2]. Cross-reacting antibodies [3] and
different immunogenicities of the large number of different serotypes may
complicate interpretation of the response further. The undoubted success of the
polysaccharide-protein conjugated vaccine Prevnar may hide the response to the
pure polysaccharide vaccine and with the initial reports of a polysaccharide-protein
conjugated vaccine developed for 15 serotypes, availability of Pneumovax may
become limited [4].
Protection against Salmonella Typhoid fever currently involves the immunization
of at risk populations living in areas with endemic Salmonella fever and of visitors
to such regions with a polysaccharide vaccine. The vaccines are targeted to the
capsular polysaccharide Vi antigen [5]. Measurement of Typhi Vi antibodies may
be a suitable additional candidate for the assessment of the response to
polysaccharide antigens because (1) interpretation is less complicated due to lack
of multiple serotypic components and thus less cross reactivity, (2) there is no
conjugated polysaccharide vaccine currently in routine use globally, and (3) the pre
Typhi Vi vaccination concentrations should be generally low in most populations
[6,7,8].
Article No~e00333
2http://dx.doi.org/10.1016/j.heliyon.2017.e00333
2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
It has been reported that 95% of healthy volunteers vaccinated with Typhim Vi
achieved a >3 fold increase (FI) in the concentration of Typhim Vi antibodies
between pre and post vaccination [6]. Sanchez-Ramon et al. recently reported that
a 3FI could aid differentiation of patients with common variable immunodeficiency
(CVID) from healthy volunteers and those with hypogammaglobulinemia (HYPO)
[8].
In the present study, we compared the response to Typhi Vi vaccination in both
children and adult control groups to that measured in patients with primary
immunodeficiencies (PID). In addition we compared the responses between
individuals with CVID or HYPO.
2. Materials and methods
2.1. Control and patient populations
Patients who were referred to the Department of Immunology, Medical Research
Institute (MRI), Colombo, Sri Lanka for routine immunological evaluation
between August 2011 and December 2013, were recruited to the study.
For all participants, a blood sample was drawn for baseline pre Typhi Vi
vaccination antibody concentrations. All individuals were vaccinated with Typbar
®
(Barat Biotech, India). Approximately 28 days post Typhi Vi vaccination, blood
was drawn from all subjects for post vaccination analysis. Assessment of Typhi Vi
vaccination did not form part of the routine immunological evaluation. All samples
were stored at −80 °C.
These patients, all of whom presented with recurrent infections, were divided into
the following groups:
1. Control group for adults (n = 24).
2. Control group for children (n = 20).
3. Adult PID group (1HYPO and 8CVID patients; n = 9).
4. Children PID group (8HYPO and 1CVID patients; n = 9).
The demographics and characteristics of each group are shown in Table 1.
Both CVID and HYPO patients were diagnosed according to the European Society
of Immunodeficiencies (ESID) and the Pan American Group for Immune
deficiency (PAGID) criteria [9,10,11]. CVID was defined as a male or female
patient with a marked decrease (at least 2 SD below the mean for age) in serum IgG
and IgA, onset of immunodeficiency at greater than 2 years of age, absent
isohemagglutinins and/or poor response to vaccines with the exclusion of defined
causes of hypogammaglobulinemia.
Article No~e00333
3http://dx.doi.org/10.1016/j.heliyon.2017.e00333
2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Table 1. Demographics and clinical characteristics of all groups used in this study.
Adult control group Adult PID group Pvalue Children control group Children PID group Pvalue
Number of patients 24 9 –20 9 –
Gender (M:F) 7:17 5:4 NS 9:11 5:4 NS
Age years (median, range) 38 (18–54) 30 (22–50) NS 7 (5–16) 6 (5–12) NS
IgG (median, range; g/L) 9.8 (6.0–16.4) 3.0 (0.04–5.1) <0.0001 10.8 (7.1–18.2) 5.1 (3.3–5.6) <0.0001
IgA (median, range; g/L) 2.6 (0.7–3.7) 0.16 (0.06–3.2) 0.0005 1.3 (0.45–3.5) 0.5 (0.08–0.91) 0.0012
IgM (median, range; g/L) 1.1 (0.5–2.8) 0.41 (0.016–1.5) 0.002 1.1 (0.55–2.5) 0.5 (0.18–1.2) 0.001
NS means not significant (p> 0.05).
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2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
All samples were taken before administration of any antibody replacement therapy.
2.2. Ethics approval
Informed written consent was obtained from all participants and studies were
performed in accordance with the Declaration of Helsinki. All procedures were
approved by the local ethics committee (Ethics Review Committee of the Medical
Research Institute, Colombo).
2.3. Measurement of Typhi Vi IgG antibodies
Anti Typhi Vi IgG were measured using the VaccZyme Salmonella Typhi Vi IgG
ELISA (The Binding Site Group, Birmingham, UK). The assay was run according
to manufacturer’s instructions. The measuring range of the assay was 7.4–600 U/
mL. Fold increase in concentration (FI) was calculated using the following
formula: Post vaccination concentration/pre vaccination concentration. For the
purpose of statistical analysis, all values <7.4 U/mL were given a value of 7.4 U/
mL and as a consequence all FI are represented as “at least”the FI achieved. FI in
concentration was assessed using a cutoff of 3 [6,8]. Responders were defined as
individuals obtaining a FI > 3 and non responders <3. The term “concentration”
refers to the concentration of Typhi Vi IgG antibodies.
2.4. Statistical analysis
Shapiro-Wilks, Mann Whitney U, Wilcoxon tests and ROC analysis were
performed using Prism Graphics Program. A p<0.05 was considered statistically
significant.
3. Results
3.1. Clinical characteristics of control and patient groups
Table 1 show the demographics and characteristics of the groups used in this study.
The ages and genders were not significantly different between the control groups
and the PID groups. Serum IgG, IgA and IgM concentrations were significantly
lower for both PID groups compared to their appropriate control groups.
3.2. Typhi Vi response in children and adult control groups
The median pre Typhi Vi vaccination concentrations are shown in Table 2. The pre
Typhi Vi vaccination concentrations were divided into concentration ranges and
the percentage of individuals in those ranges calculated (Fig. 1). In both control
groups, >95% of the individuals had Typhim Vi concentrations <100 U/mL
with the exception of 2 individuals in the adult control group (119 U/mL and
270 U/mL).
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2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Table 2. Characteristics of the Typhi Vi responses.
Responses Adult control group Adult PID group Pvalue Children control group Children PID group Pvalue
Pre vaccination (median 95% CI, U/mL) 10 (7.4–232) 7.4 (7.4–100) NS 11 (7.4–28) 9 (7.4–179) NS
Post vaccination (median 95% CI, U/mL) 519 (80–2779) 11 (7.4–1746) 0.03 679 (60–3029) 219 (12–815) 0.009
FI (median 95% CI, U/mL) 32 (5–135) 2 (1–56) 0.002 59 (7–236) 18 (1–56) 0.006
NS means not significant (p> 0.05).
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2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
The response to Typhi Vi vaccination is shown in Fig. 2 and Table 2. In the two
control groups there was significant increase in Typhi Vi concentration post
vaccination (p<0.0001) with>94% achieving ≥3FI(Fig. 2A and C).
3.3. Typhi Vi response in children and adult primary immuno-
deficiency groups
There were no significant differences between the pre Typhi Vi vaccination
concentrations in either PID groups and the appropriate control group (P= 0.1–0.5,
Table 2). The response to Typhi Vi vaccination was significantly lower in both the
children and adult PID groups when compared to their control groups (Fig. 2B and
D and Table 2).
11% and 55% of the children and adult PID groups respectively did not obtain a
response >3 FI and of the individuals with >3 FI, 25% of each PID group had post
[(Fig._1)TD$FIG]
Fig. 1. Baseline Typhi Vi IgG concentrations in children and adult control groups. The Typhi Vi pre
vaccination concentrations were determined in the two control groups and separated into concentration
ranges. The % individuals in the different concentration ranges were calculated. (A) Adult control group
(n = 24) and (B) Children control group (n = 20).
Article No~e00333
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2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Typhi Vi vaccination concentrations lower that the lower limit of the respective
normal ranges (<80 U/mL and <60 U/mL respectively, Table 2).
3.4. Comparison of children vs adult responses in the control
groups
The maximum pre Typhi Vi vaccination concentration was lower in children than
adults (<39 U/mL vs <300 U/mL, Fig. 1) but there were no significant differences
between the median pre Typhi Vi or post Typhi Vi vaccination concentrations (p>
0.3). The FI was higher in children compared to adults but did not reach statistical
significance (p= 0.06).
3.5. Comparison of responses for CVID and HYPO
When the PID patients were divided into those with HYPO and those with CVID,
both groups had a significantly lower median FI post Typhi Vi vaccination than the
control groups (19, 95% CI 5–56 vs 59, 95% CI 7–236; p= 0.01 and 1, 95% CI
1–56 vs 32, 95%CI 5–135; p= 0.005 respectively, Fig. 3). A 3 FI aided
differentiation of the antibody responses between the CVID and HYPO groups and
their control groups (AUC: 0.83, 95% CI: 0.65–1.00, p= 0.005 and 0.81, 95% CI:
0.65–0.97, p= 0.01 respectively).
[(Fig._2)TD$FIG]
Fig. 2. Responses to Typhi Vi vaccination in control groups and PID groups. Typhi Vi responses were
divided into <3 or>3 FI and represented as a percentage for (A) Adult control group, (B) Adult PID
group, (C) Children control group and (D) Children PID group.
Article No~e00333
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2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
4. Discussion
The failure to respond to a polysaccharide vaccine is a reflection of a defective
adaptive immune system in response to polysaccharide antigens and may leave an
individual at risk of recurrent infections. The IgG response to Pneumovax is
currently used to assess the ability to produce polysaccharide antigen antibodies
but this may have shortcomings. The IgG response to Typhi Vi vaccination may
represent an additional tool to assess the response to a polysaccharide antigen.
The Typhi Vi pre vaccination concentrations were very low in the two control
groups with >95% possessing concentrations <100 U/mL. This is in agreement
with previous reports [6,7,8] and suggests that the pre vaccination concentration
of Typhi Vi antibodies may not be a inhibiting factor for achieving a>3 FI as has
been observed for the response to Pneumovax [2]. Two individuals in the adult
control group had pre Typhi Vi vaccination concentrations exceeding 100 U/mL. It
is possible that they had had prior contact with the pathogen or had received a
previous vaccination. Ferry and colleagues identified 2/23 individuals with high
concentrations Typhim Vi antibodies pre vaccination. One individual had suffered
a severe systemic illness while holidaying in Asia with possible exposure to S.
typhi. The other individual had visited the tropics several times and so it was
possible they had been vaccinated in the past [6].
Robust responses were observed in both children and adult control groups and
were higher in children. A strength of the present study is the inclusion of both
children and adult PID patients in which the responses were significantly lower
[(Fig._3)TD$FIG]
Fig. 3. Responses to Typhi Vi vaccination in control groups, HYPO and CVID patients. Typhi Vi
responses were assessed in the Children control group (n = 20), Adult control group (n = 24), HYPO (n
= 8) and CVID (n = 8) groups.
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2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
than in their respective control groups. The data from the childrens population is of
particular interest clinically given the wide spread use of Prevnar in childhood
vaccination schedules and the complication it may cause in interpretation of the
response to Pneumovax.
Differentiation between HYPO and CVID populations is of particular importance
to initiate timely, correct therapy and is recommended in guidelines [12]. Sanchez
Ramon et al. reported the differentiation of those with severe antibody deficiencies
from those with a milder primary immunodeficiency and healthy controls. In this
study we observed similar results. CVID patients had a significantly lower
response than HYPO patients and the control group with 5/8 (63%) Typhi Vi IgG
concentrations lower that that obtained by any HYPO patient. The utility of using a
3 FI to discriminate CVID patients was comparable to that reported (AUC 0.83 vs
0.99) [8].
The measurement of the IgG response to Typhim Vi
TM
in parallel to Pneumovax
TM
may provide clearer understanding of T cell independent responses and potentially
the diagnosis of Specific Antibody Deficiency (SAD) [1]. Schaballie and
colleagues recently identified groups of individuals with both differing and similar
responses to Typhim Vi
TM
and Pneumovax
TM
vaccines [13]. In the individuals
with abnormal responses to both Typhim Vi
TM
and Pneumovax
TM
, one patient had
prolonged otorrhea [13,14] which may be indicative of SAD.
A limitation to this study is the size of the patient groups although the data shows
concordance to previous studies [6,8]. A larger study will allow discrimination of
patients with other defined PIDs based on the response to Typhi Vi vaccination.
In conclusion we demonstrate that measurement of antibodies raised in response to
Typhi Vi vaccination can identify responders and non responders in both children
and adult populations. In addition we show that the response to Typhi Vi can
discriminate some individuals with CVID from those with HYPO. We propose that
the measurement of Typhi Vi antibodies may provide an additional tool for the
assessment of the response to a polysaccharide vaccine.
Declarations
Author contribution statement
Jeevani Kumarage: Conceived and designed the experiments; Performed the
experiments.
Suranjith Seneviratne: Conceived and designed the experiments; Wrote the paper.
Vijitha Senaratne, Amitha Fernando, Kirthi Gunasekera, Bandu Gunasena:
Performed the experiments.
Article No~e00333
10 http://dx.doi.org/10.1016/j.heliyon.2017.e00333
2405-8440/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Padmalal Gurugama: Conceived and designed the experiments.
Sudath Peiris: Conceived and designed the experiments; Contributed reagents,
materials, analysis tools or data.
Stephen Harding, Antony R. Parker: Analyzed and interpreted the data;
Contributed reagents, materials, analysis tools or data; Wrote the paper.
Nilhan Rajiva de Silva: Conceived and designed the experiments; Performed the
experiments; Wrote the paper.
Competing interest statement
The authors declare the following conflict of interests: Antony R. Parker and
Stephen Harding are employees of the Binding Site Group Limited. The other
authors declare no conflict of interests.
Funding statement
This research did not receive any specific grant from funding agencies in the
public, commercial, or not-for-profit sectors.
Additional information
No additional information is available for this paper.
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... Alternative new antigen immunization to determine polysaccharide vaccines responses, such as Typhim Vi (TV) vaccines, is now being considered for diagnostic use. The response to TV vaccines has been reported in healthy populations and documented in patients with both PID and secondary immunodeficiency (SID) (1,2,(13)(14)(15)(16)(17). Furthermore, the use of a combination of two different polysaccharide vaccines to assess antibody deficiency may be of interest. ...
... TV is a capsular polysaccharide vaccine, administrated to populations at risk of developing typhoid fever or to individuals traveling to endemic areas, licensed in 1988 for assessment of adaptive immunity in adults and children > 18 months of age (4,13). Given the lack of a reliable anti-typhi Vi IgG standardization, several studies have measured the pre-and post-vaccination concentration ratio, demonstrating a median 3-fold increase in more than 95% of the cohorts (14,15). Similarly, the utility of evaluation for humoral immune response patients with PID was shown in recent studies (2,3,8,10,13). ...
... At present, there is very little evidence supporting TV vaccination for the assessment of adaptive immunity in a pediatric population (14). It has been shown that baseline concentrations of TV IgG are low in children (14,15). ...
Measurement of Typhim Vi IgG as a Diagnostic Tool to Determine Anti-polysaccharide Antibody Production Deficiency in Children
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Full-text available
  • Apr 2019
Background: The assessment of specific polysaccharide antibody production plays a pivotal role in the diagnosis of humoral primary immunodeficiencies (PID). The response to 23-valent pneumococcal vaccine (PPV) remains the gold standard for the diagnosis of polysaccharide antibodies. However, in Spain, the interpretation of pure polysaccharide 23-valent immunization is hampered by the high endemicity of pneumococcal disease and the generalization of the 13-valent adjuvant pneumococcal vaccination. Specific Typhim Vi vaccination (TV) immunoglobulin G IgG response to immunization is useful in adult PID, but there is no data regarding children. Objectives: To evaluate the clinical utility of TV IgG production as a diagnostic tool to determine anti-polysaccharide antibody production deficiency in children, when the response to PPV is unclear and isolated determination of serotypes is unfeasible. Methods: We conducted a single-institution prospective observational study on 61 children with recurrent infections. Baseline specific antibodies against PPV and TV were evaluated. In 28 children (46%), the response to the production of antibodies confirmed a clinical suspicion of humoral PID, and they were therefore immunized with 23-valent pneumococcal vaccine and Typhim Vi. Both specific antibody responses were measured by ELISA (The Binding Site Group Ltd, Birmingham, UK) using previously published cut-offs. Results: Seventy percent of the 61 children displayed baseline PPV IgG > 27 mg/L, whereas only 8% showed TV IgG > 28 U/mL (p < 0.0001). Twenty-one of 28 children (75%) achieved a 3-fold increase in post-vaccination TV IgG levels, whereas only 3% achieved a 4-fold increase in PPV IgG post vaccination, mainly due to high baseline PPV IgG titers. When we classified children according to their response to TV as responders or non-responders and compared this with the well-known clinical warning signs of the Jeffrey Modell Foundation. The proportions of children with history of pneumonia and the need for intravenous antibiotics were significantly higher in TV IgG non-responders than in TV IgG responders (p = 0.02 and p = 0.01, respectively). Conclusion: Response to TV can be considered an ancillary diagnostic tool to determine polysaccharide antibodies in children, particularly when isolated determination of pneumococcal serotypes is not feasible. TV provides a useful asset for clinicians in the era of conjugate PPV vaccination, with clinical relevance. Further research is warranted for validation.
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... Solutions provided by measurement of response to ViCPS vaccines Lack of consensus analytical approach to measure response to Pneumovax®23 makes inter-laboratory comparisons difficult ELISA based technology is consistently used to measure response to ViCPS Analytical discrepancies are evident between techniques used to determine antibody concentrations to individual serotypes and when compared to the overall antibody response to all Pneumovax®23 containing serotypes (Janssen et al., 2014;Reynolds et al., 2015;Lopez et al., 2016;Dziadzio et al., 2017) Consistency has been demonstrated between laboratory designed tests (LDT) and commercially available ELISAs (Bausch-Jurken et al., 2017) Development of normal reference ranges for a healthy population has proven difficult in the background of prevalent pneumococcal disease (Hare et al., 2009;Orange et al., 2012;Bonilla et al., 2015) Published normal reference ranges are available. Cut-offs to identify responders and non-responders have been identified (Ferry et al., 2004;Sánchez-Ramón et al., 2016;Bausch-Jurken et al., 2017;Kumarage et al., 2017). High baseline pneumococcal antibody concentrations are prevalent and affects interpretation of response to Pneumovax®23 (Hare et al., 2009) Low baseline concentrations of Typhi Vi IgG antibodies has been demonstrated in areas where disease prevalence is low and where it is endemic (Ferry et al., 2004;Sánchez-Ramón et al., 2016;Kumarage et al., 2017) Use of pneumococcal conjugate vaccines in immunisation and re-immunisation schedules have made the interpretation of antibody response to Pneumovax23® potentially challenging: misleadingly elevated responses to serotypes contained in conjugated pneumococcal vaccines are evident in individuals who have previously received the conjugated vaccine, masking a true polysaccharide response (Janssen et al., 2014; Limited availability of conjugated vaccines against typhoid fever makes interpretation of antibody response to ViCPS less complicated (Szu, 2013;MacLennan et al., 2014;Mitra et al., 2016;Jin et al., 2017) Conjugated vaccines are only licensed in India and China and their use will be more restricted than conjugated pneumococcal vaccines, especially in countries without endemic typhoid fever (Szu, 2013;MacLennan et al., 2014;Mitra et al., 2016;Jin et al., 2017). ...
... Cut-offs to identify responders and non-responders have been identified (Ferry et al., 2004;Sánchez-Ramón et al., 2016;Bausch-Jurken et al., 2017;Kumarage et al., 2017). High baseline pneumococcal antibody concentrations are prevalent and affects interpretation of response to Pneumovax®23 (Hare et al., 2009) Low baseline concentrations of Typhi Vi IgG antibodies has been demonstrated in areas where disease prevalence is low and where it is endemic (Ferry et al., 2004;Sánchez-Ramón et al., 2016;Kumarage et al., 2017) Use of pneumococcal conjugate vaccines in immunisation and re-immunisation schedules have made the interpretation of antibody response to Pneumovax23® potentially challenging: misleadingly elevated responses to serotypes contained in conjugated pneumococcal vaccines are evident in individuals who have previously received the conjugated vaccine, masking a true polysaccharide response (Janssen et al., 2014; Limited availability of conjugated vaccines against typhoid fever makes interpretation of antibody response to ViCPS less complicated (Szu, 2013;MacLennan et al., 2014;Mitra et al., 2016;Jin et al., 2017) Conjugated vaccines are only licensed in India and China and their use will be more restricted than conjugated pneumococcal vaccines, especially in countries without endemic typhoid fever (Szu, 2013;MacLennan et al., 2014;Mitra et al., 2016;Jin et al., 2017). ...
... Independent studies have reported low baseline concentrations of Typhi Vi IgG antibodies in children and adult blood donors (median children 1.4 AU/mL, median adults 5.3 AU/mL, assay measuring range of 0-95 AU/mL and median adult 8.6 U/mL, assay measuring range 7.4-600 U/mL) (Ferry et al., 2004;Sánchez-Ramón et al., 2016). The percentage of individuals with baseline concentrations below assay measuring ranges has been reported to be 40-71% ( Fig. 1) (Parker et al., 2014;Kumarage et al., 2017;Evans et al., 2018)) and age specific adult baseline concentrations suggest peaks in concentration between 32-41 years and 72-81 years (Parker et al., 2014). Median baseline Typhi Vi IgG concentrations are generally higher in adults compared to children (Kim et al., 1995;Ferry et al., 2004;Parker and Harding, 2016;Kumarage et al., 2017) and the range of concentrations wider (7.4-300 U/mL vs. 7.4-39 U/mL assay measuring range 7.4-600 U/mL) (Kumarage et al., 2017), however, confirmation of this trend in larger cohorts is required (Fig. 1). ...
Measurement and interpretation of Salmonella typhi Vi IgG antibodies for the assessment of adaptive immunity
Article
Full-text available
  • May 2018
  • J IMMUNOL METHODS
Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT).
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... Recent studies in PID indicate that the response to Typhim Vi (TV), a pure polysaccharide S. typhi vaccine, might act as a neoantigen in several populations and non-endemic areas [16], which could reliably be measured at diagnosis and in patients receiving IgRT. In commercial IgRT preparations, IgG TV is undetectable [17]. ...
... Therefore, the detection of TV IgG response in these patients is feasible. The utility of TV has been mainly focused on diagnosis [17,21,28,29], but it may also be informative of humoral reconstitution in individuals receiving IgRT, which is other distinctive feature of SID, mainly in a proportion of lymphomas and after progenitor cells transplantation [12,28]. This could be particularly relevant, as our very preliminary results show the value of booster TV Ab response as a marker of humoral reconstitution that help to decide IgRT cessation, whereas currently, discontinuation of IgRT is based on clinical data. ...
Evaluation of Polysaccharide Typhim Vi Antibody Response as a predictor of Humoral Immunodeficiency in Haematological Malignancies
Article
Full-text available
  • Nov 2019
An increasing healthcare challenge in the management of haematological malignancy (HM) is secondary immunodeficiency. From January 2019, the EMA included the evaluation of specific antibody (Ab) responses to better select patients for IgRT. We evaluated Ab responses to pneumococcal and Salmonella typhi pure polysaccharide immunization in a cohort of 42 HM patients and 24 healthy-controls. Pre-post specific Ab concentrations were measured by ELISA at 4 weeks. Globally, significantly lower TV seroprevalence (9%) compared to PPV (76%) (p < .001) was observed. TV non responders (88%) were higher than PPV non responders (62%) (p < .0001) and correlated better to infectious history. By ROC analysis, pre-post 5-fold TV increase was the best cut-off to discriminate HM with recurrent infections and controls (sensitivity 91%, specificity 100%). Despite the small sample cohort, our results suggest that specific anti-S typhi Ab response is a useful complementary assay in the diagnosis and management decision of SID to HM.
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... Recent studies have made an enormous effort to establish cut-off values and alternative strategies for an adequate evaluation of T-cell independent humoral response [19][20][21]. Our group and others [11,22,23] have proposed the Ab production to pure polysaccharide Vi from Salmonella Typhi as a complementary biomarker that allows to assess more accurately Ab response in patients with preserved immunological memory, either because they had previously been vaccinated with a pneumococcal conjugate vaccine (T-dependent response) or because previous immune competence (past infection or nasopharyngeal carriers of pneumococcus). This is in contrast to PID patients, in which TV and PPV show acceptable concordance and give complementary information [8,10,23]. ...
Typhim vi immunization assists to discriminate primary antibody responses in hematological malignancies
Article
Full-text available
  • May 2020
Assessment of specific antibody (Ab) production to polysaccharide antigens is clinically relevant, identifying patients at risk for infection by encapsulated bacteria and thus enabling a more rigorous selection of patients that can benefit of immunoglobulin replacement therapy. Classically, the gold-standard test is the measurement of antibody production to pure polysaccharide pneumococcal (PPV) immunization. Several factors, including introduction of conjugate vaccination schedule, serotyping analysis, high baseline Ab levels, have hindered the evaluation of polysaccharide antigens. This is even more difficult in secondary immunodeficiencies (SID), where patients can show secondary responses despite lack of primary antibody responses and present with recurrent or severe infections. Assessment of specific Ab production to pure Salmonella typhi Vi polysaccharide (TV) immunization has been proposed as a complementary test to PPV, given its low seroprevalence. To set the optimal cut-off value for PPV and TV response in SID, we tested different biostatistical methodologies, including ROC analysis, Youden index, Union index and Closest-topleft in a cohort of 42 SID patients and 24 healthy controls. The statistically chosen cut-offs value pre-post TV Ab ratio was ≥5, (sensitivity of 90%, specificity of 100%) and a postvaccination TV concentration of 28.5 U/mL (sensitivity of 90%, specificity of 95%), showing relevant clinical correlate. •Typhim Vi response have been proposed as a new strategy for the assessment of specific polysaccharide antibody response in SID due to HM. •Different biostatistical methodologies may stablish the best cut-off value to discriminate Typhim Vi response. •Typhim Vi IgG responses may better discriminate primary Ab responses showing relevant clinical correlate.
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... In this study, we have extended the utility of the observations in S anchez-Ram on and Kumarage studies to more than hypogammaglobulinaemia and CVID patients, with the inclusion of patients diagnosed with primary and secondary immunodeficiencies [7,25]. Bausch-Jurken recently reported the assessment of Typhim Vi V R response in patients treated with rituximab [15]. ...
Measurement of Typhi Vi antibodies can be used to assess adaptive immunity in patients with immunodeficiency: Use of Typhi Vi in immunodeficiency
Article
Full-text available
  • Jan 2018
  • CLIN EXP IMMUNOL
Vaccine specific antibody responses are essential in the diagnosis of antibody deficiencies. Responses to Pneumovax II are used to assess the response to polysaccharide antigens but interpretation may be complicated. Typhim Vi®, a polysaccharide vaccine for Salmonella typhoid fever, maybe an additional option for assessing humoral responses in patients suspected of having an immunodeficiency. Here we report a UK multicentre study describing the analytical and clinical performance of a Typhi Vi IgG ELISA calibrated to an affinity purified Typhi Vi IgG preparation. Intra- and inter-assay imprecision were low and the assay was linear between 7.4-574 U/mL (Slope=0.99-1.00; R²>0.99). 71% of blood donors had undetectable Typhi Vi IgG antibody concentrations. Of those with antibody concentrations >7.4U/mL, the concentration range was 7.7-167 U/mL. In antibody deficient patients receiving antibody replacement therapy the median Typhi Vi IgG antibody concentrations were <25 U/mL. In vaccinated normal healthy volunteers, the median concentration post vaccination was 107 U/mL (range 31-542U/mL). 8/8 (100%) had post vaccination concentration increases of at least 3-fold and 6/8 (75%) of at least 10-fold. In an antibody deficient population (n=23), only 30% had post vaccination concentration increases of at least 3-fold and 10% of at least 10-fold. The antibody responses to Pneumovax II and Typhim Vi® correlated. We conclude that IgG responses to Typhim Vi® vaccination can be measured using the VaccZyme Salmonella typhi Vi IgG ELISA, and that measurement of these antibodies maybe a useful additional test to accompany Pneumovax II responses for the assessment of antibody deficiencies. This article is protected by copyright. All rights reserved.
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Variable Immunodeficiency Study. (Evaluation of two European cohorts within a variety of clinical phenotypes)
Article
  • Apr 2020
  • IMMUNOL LETT
Introduction Given the wide heterogeneity of common variable immunodeficiency (CVID), several groups have proposed clinical and immunological classifications to better define follow-up and prognostic algorithms. The present study aims to validate recent clinical and laboratory algorithms, based on different combinations of CVID biomarkers, to provide more personalized treatment and follow-up strategies. Methods We analysed clinical and immunological features of 80 patients with suspected or diagnosed CVID, in two reference centres of Portugal and Spain. Clinical manifestations were categorized into clinical phenotyping proposed by Chapel et al [1]. that included cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications. Results 76% of patients in our cohort entered one of the four categories of clinical phenotyping, without overlap (cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications). The most prominent phenotype was “cytopenia” (40%) followed by “polyclonal lymphocytic infiltration” (19%). The remaining 24% of our cohort had overlap of 2 clinical phenotypes (cytopenia and unexplained enteropathy mainly). A delay of CVID diagnosis in more than 6 years presented 3.7-fold higher risk of developing lymphoproliferation and/or malignancy (p < 0.05), and was associated with increased CD8+CD45RO + T-lymphocytes (p < 0.05). An association between decreased switched-memory B cells with lymphoproliferation and malignancy was observed (p < 0.03 and p < 0.05, respectively). CD4 + T-lymphocytopenia correlated with autoimmune phenotype, with 30% prevalence (p < 0.05). HLA-DR7 expression was related to the development CVID in early life in our patients (13 vs 25 years), and DQ2.5 or DQ2.2 with unexplained enteropathy (p < 0.05). Conclusions The phenotypic and genetic study is crucial for an adequate clinical orientation of CVID patients. In these two independent cohorts of patients, classification based in clinical and laboratory algorithms, that encompasses the immunological phenotype as well as the clinical profile help to provide and get more personalized treatment and follow-up strategies
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Fifth Percentile Cutoff Values for Antipneumococcal Polysaccharide and Anti-Salmonella typhi Vi IgG Describe a Normal Polysaccharide Response
Article
Full-text available
  • May 2017
Background Serotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking. Objective To establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody, and AHA. Methods One hundred healthy subjects (10–55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3–4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method. Results Applying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre- over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (≥11.2 U/ml) and fold increase (≥2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were ½ for anti-B and ¼ for anti-A. Conclusion We establish reference cutoff values for interpretation of PPV response measured by bead-based assay, cutoff values for S. typhi Vi vaccine responses, and normal values for AHA. For the first time, the intraindividual consistency of all three methods is studied in a large cohort.
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Serotype 6B from a pneumococcal polysaccharide vaccine induces cross-functional antibody responses in adults to serotypes 6A, 6C, and 6D
Article
Full-text available
  • Sep 2016
  • MEDICINE
Cross-reactivity of pneumococcal capsular polysaccharides is a key element for formulating pneumococcal vaccines and evaluating vaccine efficacy. This study examined whether 23-valent pneumococcal polysaccharide vaccine (PPSV23), which only contains 6B, can elicit cross-functional immune responses against recently discovered serotypes (6C and 6D), as well as against 6A, in 2 adult age groups. Young adults (25–51 years; N = 28) and elderly subjects (over 65 years; N = 60) were immunized with PPSV23. Functional antibody responses were determined in pre- and postimmune sera via multiplexed opsonophagocytic killing assay against serotypes 6A/B/C/D. At postimmunization, the geometric mean opsonic indices (OIs) for 6B and nonvaccine serotypes (6A, 6C, and 6D) significantly increased in both age groups. The geometric fold increases of OIs for 6B/A/C/D significantly differed (18.2, 24.8, 3.1, and 7.1, respectively). Proportions of subjects with 4-fold increases in OIs for 6B/A/C/D were 73%, 70%, 31%, and 49%, respectively. Correlations of fold increases in OIs were highest between 6B and 6A, followed by 6B and 6D, then by 6B and 6C. Comparisons of young adults and the elderly revealed that most immunogenicity variables were higher in the former group. Our data demonstrated that 6B in PPSV23 induced cross-functional immune responses against serotypes 6A, 6C, and 6D, according to the degree of similarity in their capsular polysaccharide structures. In addition, we found significant age-related differences in PPSV23-induced cross-reactivity.
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Multicenter Study for the Evaluation of the Antibody Response against Salmonella Typhi Vi Vaccination (EMPATHY) for the Diagnosis of Anti-Polysaccharide Antibody Production Deficiency in Patients with Primary Immunodeficiency
Article
Full-text available
  • May 2016
  • CLIN IMMUNOL
Evaluation of specific antibody (Ab) response to polysaccharide antigens is essential for diagnosis of primary immunodeficiencies. We assessed the specific Ab responses to the pneumococcal-polysaccharide (PPV) and to Salmonella typhi-polysaccharide (TyphimVi) vaccines in a prospective study (EMPATHY) in patients with common variable immunodeficiency (CVID-Group, n = 22), hypogammaglobulinemia (HYPOG-Group; n = 27) and healthy controls (HC-Group; n = 16). Specific Ab concentrations in response to PPV and to TyphimVi vaccines were measured by ELISA (The Binding Site, UK), defining 3-fold increase as normal response (Ratio:3x). The RatioTyphimVi:3x was significantly greater in HC than in CVID-Group (p < 0.0001), but not than HYPOG-Group (p = 0.138). However, the RatioPPV:3x showed no significant differences among the three groups. By ROC analysis, TyphimVi better differentiated HC from CVID (AUC:0.893, IC95%: 0.791-0.996, p < 0.0001) than PPV. Our results suggest that the use of specific Ab response to TyphimVi could represent a complementary assay for the diagnosis of anti-polysaccharide Ab production deficiency in patients with CVID.
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Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update
Article
Full-text available
  • Jul 2014
Members of the European Society for Immunodeficiencies (ESID) and other colleagues have updated themulti-stage expert-opinion-based diagnostic protocol for non-immunologists incorporating newly defined primary immunodeficiency diseases (PIDs). The protocol presented here aims to increase the awareness of PIDs among doctors working in different fields. Prompt identification of PID is important for prognosis, but this may not be an easy task. The protocol therefore starts from the clinical presentation of the patient. Because PIDs may present at all ages, this protocol is aimed at both adult and paediatric physicians. The multi-stage design allows cost-effective screening for PID of the large number of potential cases in the early phases, with more expensive tests reserved for definitive classification in collaboration with a specialist in the field of immunodeficiency at a later stage.
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New diagnostic criteria for CVID
Article
Response to: Kumar R, Bhatia A. Common variable immunodeficiency in adults: current diagnostic protocol and laboratory measures. Expert Rev. Clin. Immunol. 10(2), 000-000 (2014).
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Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology
Article
  • Sep 2012
A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.
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Clinical and Experimental Immunology Patient-centred screening for primary immunodeficiency: a multi-stage diagnostic protocol designed for non-immunologists
Article
  • Aug 2006
  • CLIN EXP IMMUNOL
Vries for the Clinical Working Party of the European Society for Immunodeficiencies (ESID)* Department of Paediatrics, Jeroen Bosch Hospital (loc GZG),'s-Hertogenbosch, the Netherlands Summary Efficient early identification of primary immunodeficiency disease (PID) is important for prognosis, but is not an easy task for non-immunologists. The Clinical Working Party of the European Society for Immunodeficiencies (ESID) has composed a multi-stage diagnostic protocol that is based on expert opinion, in order to increase the awareness of PID among doctors working in different fields. The protocol starts from the clinical presentation of the patient; immunological skills are not needed for its use. The multi-stage design allows cost-effective screening for PID within the large pool of poten-tial cases in all hospitals in the early phases, while more expensive tests are reserved for definitive classification in collaboration with an immunologist at a later stage. Although many PIDs present in childhood, others may present at any age. The protocols presented here are therefore aimed at both adult phy-sicians and paediatricians. While designed for use throughout Europe, there will be national differences which may make modification of this generic algo-rithm necessary.
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Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update
Article
  • Jan 2012
  • CLIN EXP IMMUNOL
Members of the European Society for Immunodeficiencies (ESID) and other colleagues have updated the multi-stage expert-opinion-based diagnostic protocol for non-immunologists incorporating newly defined primary immunodeficiency diseases (PIDs). The protocol presented here aims to increase the awareness of PIDs among doctors working in different fields. Prompt identification of PID is important for prognosis, but this may not be an easy task. The protocol therefore starts from the clinical presentation of the patient. Because PIDs may present at all ages, this protocol is aimed at both adult and paediatric physicians. The multi-stage design allows cost-effective screening for PID of the large number of potential cases in the early phases, with more expensive tests reserved for definitive classification in collaboration with a specialist in the field of immunodeficiency at a later stage.
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Pre-clinical evaluation of a 15-valent pneumococcal conjugate vaccine (PCV15-CRM197) in an infant-rhesus monkey immunogenicity model
Article
  • Sep 2011
The incidence of invasive pneumococcal disease (IPD), caused by the approximately 91 serotypes of Streptococcus pneumoniae (PN), varies geographically and temporally as a result of changing epidemiology and vaccination patterns as well as due to regional measurement differences. Prevnar(®) (Pfizer), the first licensed pneumococcal conjugate vaccine (PCV), comprises polysaccharides (PS) from 7 serotypes conjugated to the mutant diphtheria toxin carrier protein, CRM197. In the United States and elsewhere, this vaccine has been highly efficacious in reducing the incidence of IPD caused by vaccine serotypes, however, the incidence of non-vaccine serotypes (e.g., 19A, 22F, and 33F) has increased, resulting in the need for vaccines with higher valencies. In response, 10- and 13-valent PCVs have recently been licensed. To further increase serotype coverage, we have developed a 15-valent PCV containing PS from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F conjugated to CRM197 and formulated on aluminum phosphate adjuvant. Vaccine immunogenicity was evaluated in infant rhesus monkeys since they, like human infants, respond poorly to unconjugated PN PS. Infant (2-3 month old) rhesus monkeys were vaccinated three times with PCV-15 or Prevnar(®) at 2 month intervals, and serotype-specific IgG antibodies were measured using a multiarray electrochemiluminescence (ECL) assay. The results indicate that antibody responses to PCV-15 and Prevnar(®) were comparable for the 7 common serotypes and that post-vaccination responses to PCV-15 were >10-fold higher than baseline for the 8 additional serotypes.
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