Skip Navigation

Cellular CD4 T Cell Responses to the Diphtheria- Derived Carrier Protein of Conjugated Pneumococcal Vaccine and Antibody Response to Pneumococcal Vaccination in HIV-Infected Adults

  1. Claire Rabian1,
  2. Inga Tschöpe6,
  3. Philippe Lesprit7,
  4. Christine Katlama3,
  5. Jean-Michel Molina2,
  6. Jean-Luc Meynard4,
  7. Jean-François Delfraissy9,
  8. Geneviève Cheêne6,a,
  9. Yves Lévy7,8,a, and
  10. ANRS 114 Pneumovac Study Group5,b
  1. 1Laboratoire d'Immunologie et d'Histocompatibilité, Paris
  2. 2Service des Maladies Infectieuses, St. Louis Hospital, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot, Paris
  3. 3La Pitié Hospital, Paris
  4. 4St-Antoine Hospital, Paris
  5. 5French National Agency for Research on AIDS and Viral Hepatitis, Paris
  6. 6Institut National de la Santé et de la Recherche Médicale (INSERM) U897, Bordeaux
  7. 7Service d'Immunologie, Centre Hospitalier Universitaire Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil
  8. 8INSERM U955, Université Paris, Faculté de Médecine, Créteil
  9. 9Kremlin-Bicetre Hospital, Assistance Publique-Hôpitaux de Paris, France
  1. Reprints or correspondence: Professor Yves Lévy, Service d'Immunologie, CHU Henri Mondor, Creteil France, 51 Avenue du Mal de Lattre de Tassigny, 94010 Creteil, France (yves.levy{at}hmn.aphp.fr).
 
Next Section

Abstract

Background. The French National Agency for AIDS and Viral Hepatitis Research (ANRS) 114 Pneumovac trial showed that a strategy combining a 7-valent pneumococcal conjugate vaccine (PCV) prime at week 0 followed by a 23-valent pneumococcal polysaccharide vaccine (PPV) boost at week 4 enhances the frequency and magnitude of immunoglobulin (Ig) G responses against Streptococcus pneumoniae polysaccharides (SPPs) compared with PPV alone. CD4 T cell responses specific to the diphtheria-derived carrier protein CRM197 were evaluated.

Methods. Lymphocyte proliferative responses (LPRs) and TH1 cytokine T cell responses against the diphtheriaderived carrier protein CRM197 contained in the PCV were investigated at weeks 0, 4, and 24.

Results. In the prime-boost PCV and PPV group, the magnitude of LPRs to diphtheria toxoid and CRM197 increased at week 4 (P < .001) and persisted until week 24 (P = .08 and .13, respectively, compared with week 4). Interferon-γ and interleukin-2 production to CRM197 increased significantly at week 4 (P = .02 and P < .001, respectively) and remained stable until week 24 (P = .28 and P = .08, respectively). No changes were detected in the PPV group. A strong association among the magnitude of LPRs to CRM197 at week 4, the breadth of SPP specific IgG responses at week 8 (P = .03), and sustained IgG responses at week 24 was observed. A high frequency of helper follicular CD4+CXCR5+ T cells at baseline was associated with a better LPR response to CRM197.

Conclusions. The PCV prime-elicited memory T cell responses were associated with better and sustained humoral SPP specific IgG responses.

ClinicalTrials.gov identifier. NCT00148824.

Invasive pneumococcal disease is a major cause of morbidity and mortality of human immunodeficiency virus (HIV)-1-infected patients [1–3]. Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV) reduces the incidence of invasive pneumococcal disease in immunocompetent populations. Immunization with a single dose of PPV is recommended for HIV-infected adults who have a CD4+ cell count ⩾200 cells/μL [4]. However, effectiveness of this vaccine remains highly dependent on the level of competence of the immune system [5–10]. Several studies have shown that HIVinfected patients with CD4+ cell counts <500 cells/μL have impaired immunoglobulin (Ig) G response against several Streptococcus pneumoniae polysaccharides (SPPs) compared with less immunocompromised HIV-infected patients or healthy individuals [11].

It is known that SPPs are weak immunogens, especially if the immune system is suppressed. In the recent 7-valent pneumococcal conjugate vaccine (PCV), SPP antigens are transformed to a thymus-dependent, immunologic memory-inducing form by conjugation with the diphtheriaderived carrier protein CRM197. This results in a T cell dependent immune response, characterized by increased antibody response in infants, induction of memory cells, and a booster response on subsequent antigenic exposures [12–15]. This vaccine improves the clinical efficacy in children who have a poor response to PPV [15–17].

We report the results of the randomized French National Agency for AIDS and Viral Hepatitis Research (ANRS) 114 Pneumovac study, which evaluated a prime-boost strategy combining the administration of PCV at week 0 followed by PPV at week 4 compared with the administration of PPV alone in adult HIV-1-infected patients with CD4 cell counts >200 cells/μL. Results showed that the prime-boost strategy led to a higher rate of IgG responders than the PPV alone 4 weeks after last vaccination. The breadth and magnitude of IgG responses were higher in prime-boost PCV and PPV recipients compared with PPV recipients. Moreover, these responses were sustained until weeks 24 and 96 [18].

We report the results of the immunologic evaluation of cellular immune responses elicited by the PCV. This nested study was proposed to patients enrolled in the main study and performed prospectively in a subgroup of patients randomized to the 2 groups of the study. Whether vaccine-elicited proliferative and TH1 CD4 cell responses could predict IgG responses to the SPPs was also investigated.

Previous SectionNext Section

Patients and Methods

Study design. A total of 212 HIV-infected adults were enrolled in the ANRS 114 Pneumovac trial: 106 were randomized to be vaccinated with the PCV and then with the PPV and 106 with the PPV only [18]. In 9 clinical sites in Paris, France, patients were asked to participate in an ancillary immunologic study. Sixty patients were enrolled consecutively after consent and randomized to the 2 groups of the trial. All patients gave written informed consent.

Laboratory methods. Antibody levels to each of the 7 serotypes shared by the PCV and PPV (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) and serotypes 1 and 5 (only contained in the PPV) were measured at baseline and 4 and 8 weeks after vaccination using a standardized enzyme-linked immunosorbent assay method (lower limit of quantification, 0.01μg/mL) [19]. Primary outcome included measurement of specific IgG levels to the 7 serotypes shared by the PCV and PPV [18].

Patients were classified according to the number of serotype responses after vaccination: 0, 1–2, 3–4, and 5–7 responses. Responders were defined as patients who experienced both a 2-fold postvaccination antibody increase and a level of serotype specific IgG of ⩾1 μg/mL [20].

Lymphocyte proliferative responses (LPRs) and cytokine T cell responses were investigated at baseline (week 0) and at weeks 4 and 24 in both groups. Peripheral blood mononuclear cells (PBMCs) isolated from fresh acid citrate dextrose peripheral blood samples by gradient density centrifugation were cultured in triplicate wells for 7 days in RPMI medium supplemented with 10% human AB blood group serum, male HIV tested (Biowest), with various doses of CRM197 (5, 10, and 20 μg/mL), diphtheria toxoid (DT) (10 μg/mL; Wyeth), Candidin (25 μg/mL; Biorad), or phytohemagglutinin 16 (0.5 μg/mL; Murex) in the presence of interleukin (IL)-2 (10 IU/mL; Boehringer) or in medium alone (unstimulated wells). The LPRs were quantified by incorporation of 3H-thymidine (specific activity, 185 GBq/mM, 1 μCi per well; Amersham) added during the last 18 h of culture. Results were expressed as mean counts per minute per 105 cells and as a stimulation index (SI) ratio (counts per minute in stimulated vs unstimulated cultures). Positive responses were defined both by an SI ⩾3 and a minimum 3H-thymidine incorporation of 3000 cpm as previously described [21]. Evolution of the SI throughout the study was evaluated by proliferation index ratios as defined by the ratio of SI at weeks 4 vs 0 and weeks 24 vs 0.

The PBMCs were also cultured for 48 h with CRM197 (10 μg/mL), DT (10 μg/mL), or a combination of anti-CD3 (5 μg/ mL) and anti-CD28 (0.5 μg/mL) monoclonal antibodies (Coulter Beckman) as a positive control or in medium alone as a negative control. Supernatants were collected and stored at −80°C until quantification of cytokine production (IL-2, interferon γ [IFN-γ], tumor necrosis factor-α [TNF-α], IL-4, IL-5, and IL-10) using a Cytometric Bead Assay kit (Becton Dickinson,) [22], combining a sandwich immunoassay and flow cytometry (standard curves ranging from 0 to 5000 pg/ mL). The variation of cytokine production was expressed as Δ (in picograms per milliliter) defined with the following equation: Δ = (production in stimulated wells)— (production in unstimulated wells). Negative values of this difference were replaced by 0.

The phenotype of the circulating T and B lymphocytes was evaluated at baseline, week 4, and week 24. Lymphocyte populations were enumerated in fresh whole blood EDTA samples by direct 3- or 4-color immunofluorescence with a flow cytometric analyzer (Facscalibur; Becton Dickinson) as previously described [21]. Percentages and absolute cell counts of competent (CD28+), naive (CD45RA+CCR7+), central memory (CD45RA−CCR7+), effector memory (CD45RA−CCR7−), and terminal differentiated (CD45RA+CCR7−) CD4 and CD8 T cells and naive (CD27−) and memory (CD27+) B cells were analyzed. The CD4+CXCR5+ central memory population, a marker of T-helper follicular (THf) CD4 cells [23, 24], was quantified. Antibodies used were CD45-peridinin chlorophyll protein complex (PerCP), CD3-fluorescein isothiocyanate (FITC), CD4-FITC, CD4-allophycocyanin (APC), CD4-PerCP, CD8-APC, CD8-phycoerythrin (PE), CD28-PE, CD45RO-PE, CD45RO-APC, DR-APC, CD19-FITC, CD62L-FITC, or CD57-FITC (Becton Dickinson); CD8-PerCP-Cy5.5, CD45RA-APC, or CD27-PE (Pharmingen); CCR7-PE or CXCR5-PE (RD; R&D Systems); or CD5-PE-Cy5 (Coulter Beckman).

Statistical analyses. Results of quantitative outcomes were reported as median (interquartile range [IQR]) or mean±SD. Comparisons between randomized groups for quantitative outcomes were made using the Student t test (normally distributed variables) or Wilcoxon test, and mixed linear models, applied on log transformed variables, have been fitted. Immunologic variables were compared by using the Fisher exact test for proportions and the proportional odds model for categorical variables. A logistic regression model was used to study variables associated with binary responses. All tests were 2-tailed with a global type 1 error of 5%, and analysis was performed using SAS statistical software, version 9.1 (SAS Institute).

Previous SectionNext Section

Results

Characteristics of patients. Baseline characteristics of the 60 patients involved in this study are reported in Table 1. These patients did not differ between groups or from the whole study population [18]. A total of 87% of patients received antiviral therapy.

Table 1.
View larger version:
Table 1.

Baseline Characteristics of Patients Involved in the Immunologic Substudy of the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 114 Pneumovac Trial

Phenotypic analysis of CD4 and B lymphocytes in vaccinated patients. We investigated whether vaccination induced changes in the frequency of CD4 T cell subpopulations in patients from both groups. The THf CD4 cell population characterized by the expression of CXCR5 was reported to vary in the periphery in vaccinated individuals. In the prime-boost group, before immunization the median number (IQR) of CD4+CXCR5+ THf central memory cells was 66.1 (44.3–83) cells/μL, with the CD45RO+ (median, 83.4%; IQR, 80.5%–89.2%), CD62L+ (median, 77.5%; IQR, 70.5%–83.5%), DR+ (median, 8.7%; IQR, 6.1%–12.6%), and CD57+ (median, 1.4%; IQR, 0.6%–2.1%) phenotypes. Frequency and phenotype of THf cells remained unchanged at week 4, four weeks after PCV administration (data not shown).

The distribution of naive, central memory, and effector memory CD4 and CD8 T cells did not change significantly after vaccination (at week 4) or at week 24. Median percentages of CD27+CD19+ memory B cells were 25% (IQR, 16.1%–30.5%), 21.4% (IQR, 16.4%–30.2%), and 22.3% (IQR, 14.5%–31.75%) lower at baseline, week 4, and week 24, respectively, than in control HIV-1-uninfected patients (data not shown).

LPRs to CRM197 and DT proteins. LPRs to CRM197 and DT proteins were performed to evaluate elicited CD4 T cell responses. As indicated in Table 2, and as expected, the SI to DT and CRM197 did not change throughout the study in patients in the PPV group. In contrast, in patients in the primeboost PCV and PPV group, median log10 SI to DT and CRM197 increased at week 4 (P < .001, mixed model), 4 weeks after the prime PCV. These LPRs were sustained until week 24 (P = .08 and P = .13, respectively, for comparison with week 4, mixed model) (Table 2 and Figure 1). Finally, at week 24,memory CD4 LPRs to DT and CRM197 were significantly higher in the PCV and PPV group than in the PPV group (P < .001 for both comparisons). These responses corresponded to higher proliferation index ratios in the PCV and PPV group up to 9.7 (week 4/week 0) for CRM197 and 4.8 for DT compared with the PPV group (P = .04 and P < .001, respectively). Corresponding ratios for week 24/week 0 were 5.5 for CRM197 and 3.4 for DT in the PCV and PPV group and were significantly higher than in the PPV group (P = .04 and P = .002, respectively). No significant changes of week 4/week 0 and week 24/week 0 proliferation index ratios were observed for a control candidin antigen between groups (P = .62 and P = .73, respectively; Table 3). Therefore, HIV-1-infected patients are capable of mounting significant memory responses to the carrier protein of PCV.

Table 2.
View larger version:
Table 2.

Evolution of Lymphocyte Proliferative Responses to Diphtheria Toxoid and CRM197 Proteins

Figure 1.
View larger version:
Figure 1.

Median (box plots) lymphoproliferative responses (LPR; log stimulation index) (A) and interferon-γ (IFN-γ; B) and interleukin-2 (IL-2; C) production to CRM197 in the prime-boost group (black) and the PPV group (gray). P values for comparison between randomization groups using Wilcoxon test are shown.

Table 3.
View larger version:
Table 3.

Mean Proliferative Index Ratios by Vaccination Status (Immunologic Substudy of the French National Agency for AIDS and Viral Hepatitis Research 114 Pneumovac Trial)

Cytokine production of CRM197-stimulated CD4 T cells. In the PCV and PPV group, mean (± SD) concentrations of IFN-γ production in supernatant from PBMCs stimulated with CRM197 increased from 40.4 ± 120.6 Δpg/mL at baseline to 276.1 ± 615.0 Δpg/mL at week 4 and decreased slightly to 169.6 ± 438.5 Dpg/mL at week 24. Mean (± SD) IL-2 levels were 7.0 ± 17.5 Δpg/mL at baseline, 24.1 ± 36.9 Δpg/mL at week 4, and 16.7 ± 28.8 Δpg/mL at week 24 (Figure 1).

IFN-γ and IL-2 production in response to CRM197 increased significantly from week 0 to week 4 (P = .025 and P < .001, respectively), remaining stable between weeks 4 and 24 (P = .28 and P = .08, respectively) (mixed regression model based on log-transformed data). In contrast, cytokine production by CRM197-stimulated PBMCs from patients in the PPV group did not change throughout the study. No significant changes of cytokine production in response to control candidin antigen- stimulated PBMCs were observed in both groups (data not shown). Finally, at week 24, CRM197-stimulated PBMCs from patients who received the PCV and PPV combination produced higher amounts of IFN-γ (P = .002) and IL-2 (P < .001) compared with those from PPV recipients. No significant differences between groups were reported in the production of TNF-α or TH2 cytokines by PBMCs stimulated with CRM197 (data not shown). Then, PCV elicited memory CD4 T cell responses, producing IL-2 and IFN-γ on stimulation with the PCV carrier CRM197 protein.

Association between LPRs to CRM197 protein and IgG responses to vaccination. We found a strong association between the level of LPR to CRM197 at week 4 and the breadth of IgG responses to 5–7 SPPs in patients from the PCV and PPV group (Figure 2) (P = .03). This correlation was less significant at week 24 (P = .06). The unadjusted odds ratio (OR) of the SPP specific IgG response at week 24 for the PCV and PPV vs PPV groups was 7.11 (95% confidence interval [CI], 1.4–36.2). After adjustment for a positive LPR to DT (OR, 4.45; 95% CI, 0.9–21.9) or a positive CRM197 LPR (OR, 9.69; 95% CI, 1.1–89.4) at week 4, the ORs decreased to 3.63 (95% CI, 0.6–21.8) and 3.27 (95% CI, 0.6–19.0), respectively. Although the CIs were large, a positive LPR to CRM197 at week 4 was therefore associated with sustained IgG responses to 5–7 SPPs at week 24. In a further analysis, we fitted a proportional odds model for SPP specific IgG response at week 24, using the PCV and PPV vs PPV group and LPR to CRM197 (log counts per minute) as explanatory variables. Patients with a LPR to CRM197 of 1 log higher were more likely to have sustained IgG responses to 5–7 SPPs at week 24 (OR, 4.53; 95% CI, 1.3–15.9). Finally, we found that the proportion of week 24 LPRs to DT was higher in patients from the prime-boost PCV and PPV group and in those having a baseline value of THf cells of ⩾60 × 106 cells/L (P = .04 and P = .03, respectively, in multivariate logistic model) (Table 4).

Figure 2.
View larger version:
Figure 2.

Lymphoproliferative responses (LPRs) to CRM197 at week 4 and proportion of antibody responders at week 8 (A) and week 24 (B) in patients from the prime-boost PCV and PPV group. Test of association between LPRs to CRM197 at week 4 and 5–7 antibody responders using Fisher's exact test found P = .03 for week 8 and P = .06 for week 24. Patients were classified according to the number of serotype responses after vaccination: 0, 1–2, 3–4, and 5–7 responses. Negative LPRs are represented in black and positive LPRs in gray.

Table 4.
View larger version:
Table 4.

Determinants of Response to Diphtheria Toxoid at Week 24 Based on a Logistic Model

Previous SectionNext Section

Discussion

The ANRS 114 Pneumovac trial showed that a strategy combining a prime PCV followed by a boost PPV enhances the frequency and magnitude of IgG responses against SPPs compared with the recommended PPV alone in 212 HIV-1-infected patients [18]. We show herein that the breadth and magnitude of IgG responses were associated with diphtheria-specific memory functional CD4 T cell responses. This study demonstrates that HIV-1-infected patients are capable of mounting significant and sustained, up to 24 weeks, CD4 T cell responses, producing IL-2 and IFN-γ after vaccination.

CXCR5 is present on all circulating mature B cells and on a minor subset of CD4 TH cells with an antigen-experienced (CD45RO+) phenotype [25, 26]. We have quantified CD4+CXCR5+ THf cells, a population specifically recruited during the postboosting immune response [23, 24], and key helpers for B cell differentiation and antibody production [25–27]. In both groups, the frequency of THf cells did not change significantly after vaccination and in the long term. However, we cannot rule out their transient and early peripheral blood homing in vaccinated patients as shown in other vaccination strategies [23, 24]. Nevertheless, we found that high numbers of baseline CD4 THf cells correlated with better and sustained cellular responses to DT in patients from the primeboost PCV and PPV group (P = .03 in multivariate logistic model), suggesting that this population potentiated memory response to DT.

Antibody production against SPP is supposed to be a Tindependent process that does not induce a booster effect after revaccination [28]. In PCV, SPP antigens are transformed to a thymus-dependent immunologic memory-inducing formby conjugation with the diphtheria-derived carrier protein CRM197. We demonstrated that patients developed significant T cell responses to CRM197 and DT 4 weeks after PCV administration (specific priming response), persisting at week 24. These proliferative responses were associated with a rapid and significant increase of TH1 cytokine production at week 4 that persisted until week 24. No significant changes in the production of TH2 cytokines were noted in patients from both groups. Furthermore, our results provide strong arguments for an in vivo priming of T and B cell responses because we found a strong association between the magnitude of the LPR to CRM197 at week 4 and the breadth of IgG responses to 5–7 SPPs. T cell responses at week 4 were also associated with the persistence of week 24 specific IgG responses to 5–7 SPPs.

Several studies have shown that conjugated vaccines, such as Haemophilus influenzae type b capsular polysaccharide [29] or S. pneumonia capsular polysaccharide [30], elicit memory T cell responses in mice and healthy volunteers. In a mouse model, immunization with CRM197-conjugated pneumococcal polysaccharide (PPS) induces specific proliferative responses of lymph node lymphocytes even when the PPS-specific antibody response is weak [31]. In adult volunteers, single administration of conjugated H. influenzae type b capsular polysaccharide CRM197 induced polysaccharide and CRM197 antibodies with concomitant vigorous carrier protein-specific CD4 T cell recall responses. Cellular responses peaked 1 week after immunization and rapidly decreased within 6 weeks [29]. Similarly, single administration of PCV to adult volunteers induced vigorous CD4+ T cell proliferative responses, cytokine production, and variable serotype-specific antibody titers, whereas no proliferation was induced by unconjugated PPS [30]. Our data extended the findings of these previous studies, showing that the concept of inducing T cell memory responses using these vaccines is also valuable in HIV-1-infected patients with a median CD4 T cell count of ∼200 × 106 cells/L.

The nadir CD4 T cell counts in HIV-1-infected patients has been identified as a predictor of responses to protein vaccines [32]. We found also that CD4 T cell nadir of ∼100 × 106 cells/ L, but not CD4 T cell counts at baseline, is predictive of T cell responses to DT protein. Regarding responses to the CRM197 carrier protein of PCV, analysis showed only a trend (P = .06) in favor of the predictive value of CD4 T cell nadir, likely because of the limited number of patients involved. In contrast to a previous study [32], we did not find any correlation between the frequency of CD4+CD28+ T cells and the magnitude of LPRs in vaccinated patients. Furthermore, plasma HIV RNA viral load at baseline was not predictive of LPRs to vaccines in the prime-boost PCV and PPV group. Altogether, these data show that this strategy might be proposed to most HIV-1-C infected patients regardless of treatment status.

Immunologic responses to vaccination with either T cell-dependent or SPPs are impaired in HIV-infected adults with low CD4+ cell counts [33]. HIV-1-associated impairment in the antibody response to SPPs has been attributed to B cell defects [34]. Indeed, studies have shown that SPP antibody responses are predominantly derived from B cells expressing gene segments from the immunoglobulin variable region gene family 3 (VH3) [35, 36]. VH3 gene expression seems dysregulated in HIV infection, and B cells and serum antibodies expressing VH3 are depleted in HIV-infected individuals. In patients treated with highly active antiretroviral therapy, response to PPV qualitatively changes by a restoration of VH3 genes used in the normal SPP responses [36]. There are conflicting data on whether after administration of the PCV booster vaccination with PPV increases the affinity maturation and avidity of vaccine- elicited antibodies [37].

To further complicate matters, those types of studies are difficult to perform and interpret in the context of HIV infection. Nevertheless, our results are encouraging because they provide arguments for testing the prime-boost strategy in patients with impaired antibody responses to SPPs, such as multiracial patients or individuals with low CD4+ cell counts [38].

We and others have recently reported epidemiologic studies [39] showing that despite potent antiviral regimen strategies, the mortality and morbidity rates of HIV-1-infected patients remain high [40]. Therefore, the development of efficient vaccination strategies against bacterial pathogens such as S. pneumoniae is still an important target to improve HIV case management. Moreover, in the current guidelines, no clear validated recommendations for administering booster vaccinations to patients with the current licensed PPV vaccine exist. Altogether, the results of the main Pneumovac trial [32] and the data presented in this immunologic substudy showed that a prime-boost strategy is capable of inducing IgG responses to SPPs in HIV-1-infected patients. Moreover, in vitro cellular immune responses against the PCV demonstrate that induction of immunologic memory might represent a useful surrogate marker for vaccine efficacy.

Previous SectionNext Section

Members of the ANRS 114 Pneumovac Study Group

Scientific Committee. P. Lesprit and Y. Levy (principal investigators); G. Chêne (trial coordinator); N. Sarrazin (trial monitor); G. Pedrono (trial statistician); C. Rabian (trial immunologist); and P. Bursachi, M.-J. Commoy, J.-F. Delfraissy, F. Denis, B. Fritzell, C. Goujard, R. Salamon, R. Tubiana, and J. P. Viard.

Participating clinical departments and investigators. Hôpital Avicenne, Bobigny: A. Krivitzky, M. Bentata, S. Makki, R. Mansouri, L. Guillevin, B. Jarousse, A.-K. Klutse, G. Obenga, P. Honoré-Berlureau, Y. Baazia, and S. Soreda; Hôpital Saint- Louis, Paris: J.-P. Clauvel, E. Oksenhendler, L. Gerard, J. Delgado, J.-M. Molina, N. Colin de Verdière, P. Palmer, and I. Madelaine; Hôpital Pellegrin, Bordeaux: M. Dupon, J.-M. Ragnaud, D. Neau, I. Raymond, I. Garrigue, and J.-P. Dupin; Hôpital Necker, Paris: Ch. Boitard, J.-P. Viard, S. El Marsafy, R. Lahoulou, A. Mogenet, and C. Broissand; Hôpital de Bicêtre, Le Kremlin-Bicêtre: J.-F. Delfraissy, C. Goujard, D. Pereti, Y. Quertainmont, P. Robquin, O. Segeral, S. Poirier, M.-T Rannou, N. Idri, and C. Le Tiec; Hôpital Cochin, Paris: D. Sicard, D. Salmon, O. Launay, B. Silbermann, C. Desaint, A. Krivine, and C. Guérin; Hôpital Henri-Mondor, Créteil: A. Sobel, Y. Lévy, P. Lesprit, A.-S. Lascaux, Ch. Chesnel, C. Jung, A. Miladi, and C. Antoine; Hôpital Pitié-Salpêtrière, Paris: F. Bricaire, Ch. Katlama, I. Boubezari, S. Pierre-François, L. Schneider, C. Seulié and M.-H. Fievet; Hôpital Saint-Antoine, Paris: P.-M. Girard, A.-M. Béglé, F. Besse, R. Mouchotte, A. Charrois, and A. Duaguenel- Nguyen; Hôpital Bichat, Paris: P. Yeni, I. Fournier, S. Lariven, B. Phung, P. Ralaïmazava, Ch. Gaudebout, J. Gerbe, D. Descamps, and S. LePoole; Hôpital Gui de Chauliac, Montpellier: J. Reynes, P. André, V. Baillat, V. Le Moing, C. Merle, M. Vidal, J.-M. Fondère, and I. Roch-Torreilles; Hôpital Hôtel- Dieu, Nantes: F. Raffi, P. Morineau, C. Allavena, B. Bonnet, H. Hue, E. Guarnier, and A. Lepelletier; Hôpital Les Oudairies, La Roche sur Yon: P. Perré, O. Aubry, S. Leautez, C. Leroy, I. Suaud, A.-S. Poirier, and A. Lepelletier; Hôpital de L'Archet, Nice: P. Dellamonica, V. Rahelinirina, M.-A. Sereni, S. Benhamou, and M.-Ch. Rigault; Hôpital Purpan, Toulouse: P. Massip, B. Marchou, M. Alvarez, E. Bonnet, L. Cuzin, M. Obadia, F. Balsarin, M. Barone, M. Heraud, and I. Peyranne.

Data and Safety Monitoring Board. France Mentré, Philippe Morlat.

Coordinating Trial Centre. Institut National de la Santé et de la Recherche Médicale U897, Bordeaux, France (G. Chêne, N. Sarrazin, G. Pedrono, I. Tschöpe, G. Palmer).

Previous SectionNext Section

Acknowledgments

We thank Dr. Bernard Fritzell (Wyeth Pharmaceuticals Vaccines) for his contribution to this article. We thank Dr. M. Carmagnat for helpful discussions and L. Leca, P. Mougel, D. Merret, and V. Dufour for excellent technical assistance. We thank N. Sarrazin, O. Danet, and T. Abentin, who monitored the study database, G. Pédrono, who performed the statistical analysis of the overall trial, and C. Grondin, who performed specific statistical analyses for the revised version of the manuscript. We thank the patients and investigators of the Pneumovac trial: A. Krivitzky, M. Bentata (Avicenne, Bobigny), J. P. Clauvel, E. Oksenhendler (St. Louis, Paris), M. Dupon (Pellegrin, Bordeaux), C. Boitard, J. P. Viard (Necker, Paris), J. F. Delfraissy, C. Goujard (Kremlin-Bicêtre), L. Guillevin, B. Jarousse (Avicenne, Bobigny), D. Sicard, O. Launay (Cochin, Paris), A. Sobel, Y. Lévy (H. Mondor, Créteil), F. Bricaire, C. Katlama (Pitié, Paris), P. M. Girard (Saint Antoine, Paris), J. M. Molina, N. Colin de Verdière (St. Louis, Paris), J. M. Ragnaud (Pellegrin, Bordeaux), P. Yeni, S. Lariven (Bichat, Paris), J. Reynes (G. Chauliac, Montpellier), F. Raffi, P. Morineau (Hoôtel Dieu, Nantes), P. Perre (La Roche sur Yon), P. Dellamonica (L'Archet, Nice), P. Massip, and B. Marchou (Purpan, Toulouse).

Financial support. ANRS was the legal sponsor and main funder of the entire trial. K. Gordman and P. Giardina from Wyeth-Lederle provided purified CRM197 for this specific analysis.

Potential conflicts of interest. G.C. has received grant support and lecture fees from Boehringer-Ingelheim, Gilead, Roche, and Sanofi-Aventis. Y.L. has received lectures fees from Pfizer and GSK. All other authors: no conflicts.

Previous SectionNext Section

Footnotes

  • ↵a G.C. and Y.L. contributed equally to this work.

  • ↵b The members of the ANRS 114 Pneumovac Study Group are listed at the end of the text.

  • Received July 27, 2009.
  • Accepted November 23, 2009.
Previous Section
 

References

  1. 1.↵
    1. Frankel RE,
    2. Virata M,
    3. Hardalo C,
    4. Altice FL,
    5. Friedland G
    . Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection. Clin Infect Dis 1996;23:577-584.
    Abstract/FREE Full Text
  2. 2.
    1. Nuorti JP,
    2. Butler JC,
    3. Gelling L,
    4. Kool JL,
    5. Reingold AL,
    6. Vugia DJ
    . Epidemiologic relation between HIV and invasive pneumococcal disease in San Francisco Country, California. Ann Intern Med 2000;132:182-190.
    Abstract/FREE Full Text
  3. 3.↵
    1. Jones N,
    2. Huebner R,
    3. Khoosal M,
    4. Crewe-Brown H,
    5. Klugman K
    . The impact of HIV on Streptococcus pneumoniae bacteraemia in a South African population. AIDS 1998;12:2177-2184.
    CrossRefMedlineWeb of Science
  4. 4.↵
    1. Kovacs JA,
    2. Masur H
    . Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000;342:1416-1429.
    CrossRefMedlineWeb of Science
  5. 5.↵
    1. French N,
    2. Nakiyingi J,
    3. Carpenter LM,
    4. et al
    . 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial. Lancet 2000;355:2106-2111.
    CrossRefMedlineWeb of Science
  6. 6.
    1. Dworkin MS,
    2. Ward JW,
    3. Hanson DL,
    4. Jones JL,
    5. Kaplan JE
    . Pneumococcal disease among human immunodeficiency virus-infected persons: incidence, risk factors, and impact of vaccination. Clin Infect Dis 2001;32:794-800.
    Abstract/FREE Full Text
  7. 7.
    1. Breiman RF,
    2. Keller DW,
    3. Phelan MA,
    4. et al
    . Evaluation of effectiveness of the 23-valent pneumococcal capsular polysaccharide vaccine for HIV-infected patients. Arch Intern Med 2000;160:2633-2638.
    Abstract/FREE Full Text
  8. 8.
    1. Hung CC,
    2. Chen MY,
    3. Hsieh SM,
    4. Hsiao CF,
    5. Sheng WH,
    6. Chang SC
    . Clinical experience of the 23-valent capsular polysaccharide pneumococcal vaccination in HIV-1-infected patients receiving highly active antiretroviral therapy: a prospective observational study. Vaccine 2004;22:2006-2012.
    CrossRefMedlineWeb of Science
  9. 9.
    1. Rodriguez-Barradas MC,
    2. Musher DM,
    3. Lahart C,
    4. et al
    . Antibody to capsular polysaccharides of Streptococcus pneumoniae after vaccination of human immunodeficiency virus-infected subjects with 23-valent pneumococcal vaccine. J Infect Dis 1992;165:553-556.
    Abstract/FREE Full Text
  10. 10.↵
    1. Rodriguez-Barradas MC,
    2. Alexandraki I,
    3. Nazir T,
    4. et al
    . Response of human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy to vaccination with 23-valent pneumococcal polysaccharide vaccine. Clin Infect Dis 2003;37:438-447.
    Abstract/FREE Full Text
  11. 11.↵
    1. Ahmed F,
    2. Steinhoff MC,
    3. Rodriguez-Barradas MC,
    4. Hamilton RG,
    5. Musher DM,
    6. Nelson KE
    . Effects of human immunodeficiency virus type 1 infection on the antibody response to a glycoprotein conjugate pneumococcal vaccine: results from a randomized trial. J Infect Dis 1996;173:83-90.
    Abstract/FREE Full Text
  12. 12.↵
    1. Rennels MB,
    2. Edwards KM,
    3. Keyserling HL,
    4. et al
    . Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics 1998;101:604-611.
    Abstract/FREE Full Text
  13. 13.
    1. Dagan R,
    2. Melamed R,
    3. Zamir O,
    4. Leroy O
    . Safety and immunogenicity of tetravalent pneumococcal vaccines containing 6B, 14, 19F and 23F polysaccharides conjugated to either tetanus toxoid or diphtheria toxoid in young infants and their boosterability by native polysaccharide antigens. Pediatr Infect Dis J 1997;16:1053-1059.
    CrossRefMedlineWeb of Science
  14. 14.
    1. Ahman H,
    2. Käyhty H,
    3. Lehtonen H,
    4. Leroy O,
    5. Froeschle J,
    6. Eskola J
    . Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory. Pediatr Infect Dis J 1998;17:211-216.
    CrossRefMedlineWeb of Science
  15. 15.↵
    1. Whitney CG,
    2. Farley MM,
    3. Hadler J,
    4. et al
    . Decline in invasive pneumococcal disease after the introduction of protein polysaccharide conjugate vaccine. N Engl J Med 2003;348:1737-1746.
    CrossRefMedlineWeb of Science
  16. 16.
    1. Madhi SA,
    2. Adrian P,
    3. Kuwanda L,
    4. et al
    . Long-term immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine in immunodeficient virus infected and non-infected children in the absence of a booster dose of vaccine. Vaccine 2007;25:2451-2457.
    CrossRefMedlineWeb of Science
  17. 17.↵
    1. Bliss SJ,
    2. O'Brien KL,
    3. Janoff EN,
    4. et al
    . The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect Dis 2008;8:67-80.
    CrossRefMedlineWeb of Science
  18. 18.↵
    1. Lesprit P,
    2. Pédrono G,
    3. Molina JM,
    4. et al
    . Immunological efficacy of a prime-boost pneumococcal vaccination in HIV-infected adults. AIDS 2007;21:2425-2434.
    CrossRefMedlineWeb of Science
  19. 19.↵
    1. Wernette CM,
    2. Frasch CE,
    3. Madore D,
    4. et al
    . Enzyme-linked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Diagn Lab Immunol 2003;10:514-519.
    CrossRefMedline
  20. 20.↵
    1. Pédrono G,
    2. Thiébaut R,
    3. Ahmadou A,
    4. et al
    . A new endpoint definition improved clinical relevance and statistical power in a vaccine trial. J Clin Epidemiol 2009;62:1054-1061.
    CrossRefMedlineWeb of Science
  21. 21.↵
    1. Fournier S,
    2. Rabian C,
    3. Alberti C,
    4. et al
    . Immune recovery under highly active antiretroviral therapy is associated with restoration of lymphocyte proliferation and interferon-gamma production in the presence of Toxoplasma gondii antigens. J Infect Dis 2001;183:1586-1591.
    Abstract/FREE Full Text
  22. 22.↵
    1. Alfonzo M,
    2. Blanc D,
    3. Troadec C,
    4. Eliaszewicz M,
    5. Gonzalez G,
    6. Scott-Algara D
    . Partial restoration of cytokine profile despite reconstitution of cytomegalovirus-specific cell-mediated immunity in human immunodeficiency virus-infected patients during highly active antiretroviral treatment. Scand J Immunol 2003;57:375-383.
    CrossRefMedlineWeb of Science
  23. 23.↵
    1. Schaerli P,
    2. Willimann K,
    3. Lang AB,
    4. Lipp M,
    5. Loetscher P,
    6. Moser B
    . CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 2000;192:1553-1562.
    Abstract/FREE Full Text
  24. 24.↵
    1. Schaerli P,
    2. Loetscher P,
    3. Moser B
    . Cutting edge: induction of follicular homing precedes effector Th cell development. J Immunol 2001;167:6082-6086.
    Abstract/FREE Full Text
  25. 25.↵
    1. Kim CH,
    2. Rott LS,
    3. Clark-Lewis I,
    4. Campbell DJ,
    5. Wu L,
    6. Butcher EC
    . Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J Exp Med 2001;193:1373-1381.
    Abstract/FREE Full Text
  26. 26.↵
    1. Legler DF,
    2. Loetscher M,
    3. Roos RS,
    4. Lewis-Clark I,
    5. Baggiolini M,
    6. Moser B
    . B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med 1998;187:655-660.
    Abstract/FREE Full Text
  27. 27.↵
    1. Warnatz K
    . Dissecting CXCR5+ T cell populations: on the quest for a better understanding of B cell help during T dependent antibody responses. Eur J Immunol 2006;36:1662-1664.
    CrossRefMedlineWeb of Science
  28. 28.↵
    1. Mond JJ,
    2. Lees A,
    3. Snapper CM
    . T cell-independent antigens type 2. Annu Rev Immunol 1995;13:655-692.
    CrossRefMedlineWeb of Science
  29. 29.↵
    1. Kamboj KK,
    2. King CL,
    3. Greenspan NS,
    4. Kirchner HL,
    5. Schreiber JR
    . Immunization with Haemophilus influenzae type b-CRM(197) conjugate vaccine elicits a mixed Th1 and Th2 CD4+ T cell cytokine response that correlates with the isotype of antipolysaccharide antibody. J Infect Dis 2001;184:931-935.
    Abstract/FREE Full Text
  30. 30.↵
    1. Kamboj KK,
    2. Kirchner HL,
    3. Kimmel R,
    4. Greenspan NS,
    5. Schreiber JR
    . Significant variation in serotype-specific immunogenicity of seven-valent streptococcus pneumoniae capsular polysaccharide-CRM-197 conjugate vaccine occurs despite vigorous T cell help induced by carrier protein. J Infect Dis 2003;187:1629-1638.
    Abstract/FREE Full Text
  31. 31.↵
    1. McCool T,
    2. Harding CV,
    3. Greenspan NS,
    4. Schreiber JR
    . B- and T-cell immune responses to pneumococcal conjugate vaccines: divergence between carrier- and polysaccharide-specific immunogenicity. Infect Immun 1999;67:4862-4869.
    Abstract/FREE Full Text
  32. 32.↵
    1. Lange CG,
    2. Lederman MM,
    3. Medvik K,
    4. et al
    . Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS 2003;17:2015-2023.
    CrossRefMedlineWeb of Science
  33. 33.↵
    1. Kroon FP,
    2. van Dissel JT,
    3. Labadie J,
    4. van Loon AM,
    5. van Furth R
    . Antibody response to diphtheria, tetanus, and poliomyelitis vaccines in relation to the number of CD4+ T lymphocytes in adults infected with human immunodeficiency virus. Clin Infect Dis 1995;21:1197-1203.
    Abstract/FREE Full Text
  34. 34.↵
    1. Chang Q,
    2. Abadi J,
    3. Alpert P,
    4. Pirofski L
    . A pneumococcal capsular polysaccharide vaccine induces a repertoire shift with increased VH3 expression in peripheral B cells from human immunodeficiency virus (HIV)-uninfected but not HIV-infected persons. J Infect Dis 2000;181:1313-1321.
    Abstract/FREE Full Text
  35. 35.↵
    1. Abadi J,
    2. Friedman J,
    3. Mageed RA,
    4. Jefferis R,
    5. Rodriguez-Barradas MC,
    6. Pirofski L
    . Human antibodies elicited by a pneumococcal vaccine express idiotypic determinants indicative of V(H)3 gene segment usage. J Infect Dis 1998;178:707-716.
    Abstract/FREE Full Text
  36. 36.↵
    1. Subramaniam KS,
    2. Segal R,
    3. Lyles RH,
    4. Rodriguez-Barradas MC,
    5. Pirofski LA
    . Qualitative change in antibody responses of human immunodeficiency virus-infected individuals to pneumococcal capsular polysaccharide vaccination associated with highly active antiretroviral therapy. J Infect Dis 2003;187:758-768.
    Abstract/FREE Full Text
  37. 37.↵
    1. Anttila M,
    2. Eskola J,
    3. Ahman H,
    4. Käyhty H
    . Avidity of IgG for Streptococcus pneumoniae type 6B and 23F polysaccharides in infants primed with pneumococcal conjugates and boosted with polysaccharide or conjugate vaccines. J Infect Dis 1998;177:1614-1621.
    Abstract/FREE Full Text
  38. 38.↵
    1. French N,
    2. Moore M,
    3. Haikala R,
    4. Käyhty H,
    5. Gilks CF
    . A case control study to investigate serological correlates of clinical failure of 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults. J Infect Dis 2004;190:707-712.
    Abstract/FREE Full Text
  39. 39.↵
    1. Lewden C,
    2. Chêne G,
    3. Morlat P,
    4. et al
    . HIV-Infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007;46:72-77.
    MedlineWeb of Science
  40. 40.↵
    1. Le Moing V,
    2. Rabaud C,
    3. Journot V,
    4. et al
    . Incidence and risk factors of bacterial pneumonia requiring hospitalization in HIV-infected patients started on a protease inhibitor-containing regimen. HIV Med 2006;7:261-267.
    CrossRefMedlineWeb of Science
| Table of Contents

This Article

  1. Clin Infect Dis. (2010) 50 (8): 1174-1183. doi: 10.1086/651418
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most