No long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine

doi:10.1016/j.jaci.2015.12.1303

Journal of Allergy and Clinical Immunology

Volume 137, Issue 6, June 2016, Pages 1772-1779.e11

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https://doi.org/10.1016/j.jaci.2015.12.1303 Get rights and content

Background

A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage.

Objective

This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later.

Methods

Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization.

Results

Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage.

Conclusion

Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.

Section snippets

Study population and samples

The study design and details of FiPP (2003-2008) have been reported previously.10, 11, 12 Briefly, healthy Fijian infants (n = 552) were randomized to receive a primary series of 0, 1, 2, or 3 doses of PCV7, with half the children randomized to receive 23vPPV at 12 months of age. Children given 0 or 1 PCV7 doses during the primary series were given a catch-up PCV7 dose at 2 years of age (Table I). Between March 2011 and February 2012, families who had participated in FiPP and previously agreed

Results

Of the 552 children in the original FiPP study, the families of 437 children gave permission to be contacted for this follow-up study. There were 194 families that were contactable for this follow-up study because the population is mobile and contact details, including telephone numbers, were no longer valid. However, the families of all 194 children, now aged 5 to 7 years, provided written informed consent for this study. A nasopharyngeal swab and paired blood specimens were collected from 185

Discussion

This is the first study to comprehensively characterize the long-term effects of immune hyporesponsiveness after 23vPPV immunization in children at high risk of pneumococcal disease. In a vaccine trial in which 552 Fijian infants were vaccinated with various dose schedules of PCV7 and half were boosted at 12 months with 23vPPV, we demonstrated that 23vPPV recipients at 18 months of age were nonresponsive to a small 20% dose of 23vPPV, whereas children who had not received 23vPPV had good

References (31)

K.L. O'Brien et al.
Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates
Lancet
(2009)
C. Feldman et al.
Review: current and new generation pneumococcal vaccines
J Infect
(2014)
S. Moberley et al.
Failure to vaccinate or failure of vaccine? Effectiveness of the 23-valent pneumococcal polysaccharide vaccine program in Indigenous adults in the Northern Territory of Australia
Vaccine
(2010)
N.J. Andrews et al.
Impact and effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in the elderly in England and Wales
Vaccine
(2012)
I.D. Riley et al.
Pneumococcal vaccine prevents death from acute lower-respiratory-tract infections in Papua New Guinean children
Lancet
(1986)
F.M. Russell et al.
Hyporesponsiveness to re-challenge dose following pneumococcal polysaccharide vaccine at 12 months of age, a randomized controlled trial
Vaccine
(2010)
F.M. Russell et al.
Safety and immunogenicity of the 23-valent pneumococcal polysaccharide vaccine at 12 months of age, following one, two, or three doses of the 7-valent pneumococcal conjugate vaccine in infancy
Vaccine
(2010)
C. Satzke et al.
Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World Health Organization Pneumococcal Carriage Working Group
Vaccine
(2013)
A. Balloch et al.
Results from an inter-laboratory comparison of pneumococcal serotype-specific IgG measurement and critical parameters that affect assay performance
Vaccine
(2010)
R. Borrow et al.
Reduced antibody response to revaccination with meningococcal serogroup A polysaccharide vaccine in adults
Vaccine
(2000)

M.A. Mufson et al.

Revaccination with pneumococcal vaccine of elderly persons 6 years after primary vaccination

Vaccine

(1991)

L.A. Jackson et al.

Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older

Vaccine

(2013)

S.T. Sigurdardottir et al.

Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children

Vaccine

(2014)

K.L. O'Brien et al.

Combined schedules of pneumococcal conjugate and polysaccharide vaccines: is hyporesponsiveness an issue?

Lancet Infect Dis

(2007)

B. Henriques-Normark et al.

The pneumococcus: epidemiology, microbiology, and pathogenesis

Cold Spring Harb Perspect Med

(2013)

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2021, The Lancet Regional Health - Western Pacific
Citation Excerpt :
Opsonophagocytic assays (OPA) for these 12 serotypes were performed in a subset of participants (the first 50 paired samples per group) at the 19 and 24 month time points, using a previously published multiplexed OPA method[13] with some minor modifications. Peripheral blood mononuclear cells (PBMCs) were isolated in a subset of participants (the first 100 recruited per group) at the 18 and 24 month time points, for measurement of pneumococcal-specific Bmem by ELISPOT for seven serotypes (1, 5, 6B, 14, 18C, 19A and 23F) using an established method.[20] Nasopharyngeal swabs were collected at 18 and 24 months, and were stored and transported consistent with WHO guidelines.[21]
This study investigated the immunogenicity and impact on nasopharyngeal carriage of a single dose of PCV10 given to 18-month-old Vietnamese children. This information is important for countries considering catch-up vaccination during PCV introduction and in the context of vaccination during humanitarian crises.
Two groups of PCV-naïve children within the Vietnam Pneumococcal Project received PCV10 (n=197) or no PCV (unvaccinated; n=199) at 18 months of age. Blood samples were collected at 18, 19, and 24 months of age, and nasopharyngeal swabs at 18 and 24 months of age. Immunogenicity was assessed by measuring serotype-specific IgG, opsonophagocytosis (OPA) and memory B cells (Bmem). Pneumococci were detected and quantified using real-time PCR and serotyped by microarray.
At 19 months of age, IgG and OPA responses were higher in the PCV10 group compared with the unvaccinated group for all PCV10 serotypes and cross-reactive serotypes 6A and 19A. This was sustained out to 24 months of age, at which point PCV10-type carriage was 60% lower in the PCV10 group than the unvaccinated group. Bmem levels increased between 18 and 24 months of age in the vaccinated group.
We demonstrate strong protective immune responses in vaccinees following a single dose of PCV10 at 18 months of age, and a potential impact on herd protection through a substantial reduction in vaccine-type carriage. A single dose of PCV10 in the second year of life could be considered as part of catch-up campaigns or in humanitarian crises to protect children at high-risk of pneumococcal disease.
Immunogenicity of alternative ten-valent pneumococcal conjugate vaccine schedules in infants in Ho Chi Minh City, Vietnam: results from a single-blind, parallel-group, open-label, randomised, controlled trial
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Data are scarce from low-income and middle-income countries (LMICs) to support the choice of vaccination schedule for the introduction of pneumococcal conjugate vaccines (PCV). We aimed to compare the immunogenicity of four different infant PCV10 schedules in infants in Vietnam.
In this single-blind, parallel-group, open-label, randomised controlled trial, infants aged 2 months were recruited by community health staff in districts 4 and 7 of Ho Chi Minh City, Vietnam. Eligible infants had no clinically significant maternal or prenatal history and were born at or after 36 weeks' gestation. Participants were randomly assigned (3:3:5:4:5:4) using block randomisation, stratified by district, to one of six PCV10 or PCV13 vaccination schedules. Here we report results for four groups: group A, who were given PCV10 at ages 2, 3, 4, and 9 months (a 3 + 1 schedule); group B, who were vaccinated at ages 2, 3, and 4 months (3 + 0 schedule); group C, who were vaccinated at ages 2, 4, and 9·5 months (2 + 1 schedule); and group D, who were vaccinated at ages 2 and 6 months (two-dose schedule). Laboratory-based assessors were masked to group allocation. Blood samples were collected at different prespecified timepoints between ages 3–18 months depending on group allocation, within 27–43 days after vaccination, and these were analysed for serotype-specific IgG and opsonophagocytic responses. Participants were followed-up until age 24 months. The primary outcome was the proportion of infants with serotype-specific IgG levels of 0·35 μg/mL or higher at age 5 months, analysed as a non-inferiority comparison (10% margin) of the two-dose and three-dose primary series (group C vs groups A and B combined). We also compared responses 4 weeks after two doses administered at either ages 2 and 4 months (group C) or at ages 2 and 6 months (group D). The primary endpoint was analysed in the per-protocol population. Reactogenicity has been reported previously. This study is registered with ClinicalTrials.gov, NCT01953510, and is now closed to accrual.
Between Sept 30, 2013, and Jan 9, 2015, 1201 infants were enrolled and randomly assigned to group A (n=152), group B (n=149), group C (n=250), group D (n=202), or groups E (n=251) and F (n=197). In groups A–D, 388 (52%) of 753 participants were female and 365 (48%) were male. 286 (95%) participants in groups A and B combined (three-dose primary series) and 237 (95%) in group C (two-dose primary series) completed the primary vaccination series and had blood samples taken within the specified time window at age 5 months (per-protocol population). At this timepoint, a two-dose primary series was non-inferior to a three-dose primary series for eight of ten vaccine serotypes; exceptions were 6B (84·6% [95% CI 79·9–88·6] of infants had protective IgG concentrations after three doses [groups A and B combined] vs 76·8% [70·9–82·0] of infants after two doses [group C]; risk difference 7·8% [90% CI 2·1–13·6]) and 23F (90·6% [95% CI 86·6–93·7] vs 77·6% [71·8–82·2]; 12·9% [90% CI 7·7–18·3]). Two doses at ages 2 and 6 months produced higher antibody levels than two doses at ages 2 and 4 months for all serotypes except 5 and 7F.
A two-dose primary vaccination series was non-inferior to a three-dose primary vaccination series while two doses given with a wider interval between doses increased immunogenicity. The use of a two-dose primary vaccination schedule using a wider interval could be considered in LMIC settings to extend protection in the second year of life.
Australian National Health and Medical Research Council, and The Bill & Melinda Gates Foundation.
Effect of peripheral blood mononuclear cell cryopreservation on innate and adaptive immune responses
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Data was analysed using Xponent LX100/LX200 software. Enumeration of tetanus toxoid and diphtheria toxoid-specific memory B cells was done according to a previously published method (Licciardi et al., 2016). Briefly, freshly-isolated PBMCs were resuspended in RPMI-FBS at a concentration of 2 × 106 cells/mL and were stimulated with an antigen cocktail (Staphylococcus aureus Cowan strain – Pansorbin cells [SAC; 1:5000], 2.5 μg/mL CpG and 83 ng/mL pokeweed mitogen) for 6 days at 37 °C, 5% CO2.
Cryopreservation of blood-derived immune cells is commonly used in clinical trials to examine immunological responses. However, studies elucidating the effects of cryopreservation on peripheral blood mononuclear cell (PBMC) responses have shown inconsistent results making it difficult to draw meaningful conclusions. Therefore we sought to address this issue by comparing key innate and adaptive immune parameters between freshly-isolated and cryopreserved PBMCs from healthy adults. We examined the effect of cryopreservation on the expression of key markers on innate and adaptive immune cell populations (i.e. CD4+ and CD8+ [T cells], CD14+ [monocytes], CD19+ [B cells], CD56+ [NK cells] or CD19 + CD27+ [memory B cells]), on cytokine secretion (TNF-α, INF-γ, IL-1β, IL-10, IL-6, MCP-1 and RANTES) in cultured PBMC supernatants following stimulation with a range of Toll-like receptor (TLR) agonists, as well as on antigen-specific memory B cell enumeration by ELISpot. We found that cryopreservation had no effect on the expression of immune markers on innate and adaptive immune cells as well on the number of antigen-specific memory B cells. However, the response to TLR ligands such as FLA-ST, CpG and LPS was variable with increased cytokine production by cryopreserved PBMCs observed compared to freshly-isolated PBMCs. Our results suggest that the effect of cryopreservation on the biological response of immune cell populations needs to be carefully considered, particularly in the context of clinical studies that rely on these immune outcomes.
Pneumococcal vaccination in adult solid organ transplant recipients: A review of current evidence
2018, Vaccine
Citation Excerpt :
Functional antibody responses can be measured by opsonophagocytic assays (OPA). OPA may be particularly important in SOT recipients as these assays measure the ability of the antibodies to opsonize and kill pneumococci, which may be affected by the immunosuppression used in transplantation [43–46]. Studies in SOT recipients have examined both antibody titers and opsonophagocytic assay titers [6,20,36,41].
This narrative review summarizes the current literature relating to pneumococcal vaccination in adult solid organ transplant (SOT) recipients, who are at risk of invasive pneumococcal disease (IPD) with its attendant high morbidity and mortality.
The effect of the pneumococcal polysaccharide vaccine has been examined in several small cohort studies in SOT recipients, most of which were kidney transplant recipients. The outcomes for these studies have been laboratory seroresponses or functional antibody titers. Overall, in most of these studies the transplant recipients were capable of generating measurable serological responses to pneumococcal vaccination but these responses were less than those of healthy controls. A mathematical model estimated the effectiveness of polysaccharide vaccination in SOT recipients to be one third less than those of patients with HIV.
The evidence for the efficacy of the pneumococcal conjugate vaccine in SOT is based on a small number of randomized controlled trials in liver and kidney transplant recipients. These trials demonstrated that SOT recipients mounted a serological response following vaccination however there was no benefit to the use of prime boosting (conjugate vaccine followed by polysaccharide vaccine). Currently there are no randomized studies investigating the clinical protection rate against IPD after pneumococcal vaccination by either vaccine type or linked to vaccine titers or other responses against pneumococcus. Concerns that vaccination may increase the risk of adverse alloresponses such as rejection and generation of donor specific antibodies are not supported by studies examining this aspect of vaccine safety. Pneumococcal vaccination is a potentially important strategy to reduce IPD in SOT recipients and is associated with excellent safety. Current international recommendations are based on expert opinion from conflicting data, hence there is a clear need for further high-quality studies in this high-risk population examining optimal vaccination regimens. Such studies should focus on strategies to optimize functional immune responses.
Repeat pneumococcal polysaccharide vaccine in Indigenous Australian adults is associated with decreased immune responsiveness
2017, Vaccine
Citation Excerpt :
While there is some evidence of an adequate immunological response to revaccination, no data are available from randomised controlled trials determining clinical efficacy [6–9]. Immune hyporesponsiveness, associated with the production of attenuated serotype-specific IgG responses to vaccine serotypes, has been suggested to result following repeated polysaccharide immunisation and has been demonstrated following 23vPPV in Fijian children [10], although this was no longer apparent by 5 years of age [11]. To investigate the possibility that hyporesponsiveness following repeat vaccination may be one factor contributing to persistently high rates of pneumococcal disease in Indigenous adults, we compared the immune response following a second dose of 23vPPV in Indigenous Australians with the response following a first dose in both Indigenous and non-Indigenous Australians.
Indigenous adults residing in the Northern Territory of Australia experience elevated rates of invasive pneumococcal disease despite the routine use of 23-valent pneumococcal polysaccharide vaccine (23vPPV). We hypothesised that the limited protection from 23vPPV may be due to hyporesponsiveness as a result of vaccine failure from repeated vaccination. To explore this possibility, we evaluated the immune response to a first and second dose of 23vPPV in Indigenous adults and a first dose of 23vPPV in non-Indigenous adults.
Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline and at one month post-vaccination. Individuals were considered to have an adequate immune response if paired sera demonstrated either: a four-fold rise in antibody concentration; a two-fold rise if the post vaccination antibody was >1.3 μg/ml but <4.0 μg/ml; or a post-vaccination antibody concentration >4.0 μg/ml for at least half of the serotypes tested (12/23). Our per-protocol analysis included the comparison of outcomes for three groups: Indigenous adults receiving a second 23vPPV dose (N = 20) and Indigenous (N = 60) and non-Indigenous adults (N = 25) receiving their first 23vPPV dose.
All non-Indigenous adults receiving a first dose of 23vPPV mounted an adequate immune response (25/25). There was no significant difference in the proportion of individuals with an adequate response using our definition (primary endpoint), with 88% of Indigenous adults mounted an adequate response following first dose 23vPPV (53/60) compared to 70% having an adequate response following a second dose of 23vPPV (14/20; p = 0.05). The risk difference between Indigenous participants receiving first dose compared to non-Indigenous participants receiving first dose was significant when comparing a response threshold of at least 70% (−27%, 95% CI: −43% to −11%; p = 0.01) and 90% (−38%, 95% CI: −60% to −16%; p = 0.006) of serotypes with a positive response.
Indigenous participants demonstrated a poorer response to a first dose 23vPPV compared to their non-Indigenous counterparts, with lower IgG following a second 23vPPV dose. These findings highlight the critical need to evaluate the efficacy of future pneumococcal vaccine programs in the Australian Indigenous populations that recommend repeated doses of 23vPPV.
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2017, Plotkin's Vaccines

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: Supported by a National Institutes of Allergy and Infectious Disease grant (1R01AI085198-01A1). P.V.L. is a recipient of an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship. Y.B.C. was supported by the National Research Foundation, Singapore, under its Clinician Scientist Award (award no. NMRC/CSA/039/2011) administered by the Singapore Ministry of Health's National Medical Research Council. E.A.C. was supported by the NIHR Oxford Biomedical Research Centre. A.J.P. is a Jenner Institute Investigator and a James Martin Senior Fellow. We also acknowledge the support of the Victorian Government's Operational Infrastructure Support Program. The views expressed in this manuscript do not necessarily reflect the views of the UK Department of Health or Joint Committee on Vaccination and Immunisation.

: Disclosure of potential conflict of interest: C. Satzke receives funds from Merck, Sharp & Dohme. A. J. Pollard receives research funding from Pfizer and GlaxoSmithKline and is also chair of the UK Department of Health's Joint Committee on Vaccination and Immunisation. E. K. Mulholland serves on the advisory board for Merck & Co. The rest of the authors declare that they have no relevant conflicts of interest.

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Immune deficiencies, infection, and systemic immune disordersNo long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine

Background

Objective

Methods

Results

Conclusion

Section snippets

Study population and samples

Results

Discussion

Lancet

J Infect

Vaccine

Vaccine

Lancet

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Lancet Infect Dis

The pneumococcus: epidemiology, microbiology, and pathogenesis

Cold Spring Harb Perspect Med

Immune deficiencies, infection, and systemic immune disorders
No long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine