Vaccination anti-pneumococcique chez les sujets à risque d'infections invasives à pneumocoques et prévention de l'hyporéponse

Two vaccines are currently available for the prevention of invasive pneumococcal diseases (IPD): a polysaccharide vaccine, Pneumovax® (PPV23) and a conjugate vaccine, Prevenar13® (PCV13), inducing protection against 23 and 13 serotypes, respectively. PPV23 is considered to be weakly immunogenic, particularly in the elderly and immunocompromised patients. PCV13, however, due to the conjugation to a carrier protein, has the advantage of inducing a T-dependent immune response, not observed with PPV23 vaccine. In our work, we therefore evaluated the impact of vaccine strategies using PCV13 and PPV23 on different populations of patients at risk of IPD. In a first study, our results on anti-pneumococcal vaccination in patients with smoldering myeloma (SMM) showed that a single dose of PCV13 induces a transient immune response and long term persistence. These results suggested the use of a vaccination schedule including several doses of PCV13 or association with the PPV23. Since 2013, this combined strategy of PCV13 and PPV23 is recommended by la Haute Autorité de Santé (HAS) for patients at risk, with the following delays: a dose of PCV13 followed by a dose of PPV23, 8 weeks later. We then studied this combined vaccine strategy in patients at risk of IPD: patients with systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). Our results show a short-term immunogenicity of the combined strategy, but a protection that does not persist beyond two years. Surprisingly, antibody levels 2 years after vaccination are lower than pre-vaccine levels for RA patients. This negative effect of PPV23 on PCV13-induced immune response is called hyporesponsiveness. This phenomenon, observed in RA patients, is not found in SLE patients who received PPV23 vaccination at distance from PCV13. These results suggest that the delayed vaccination schedule (ie, PPV23 vaccination six months after PCV13 instead of two months) could inhibit the hyporesponsiveness phenomenon. In a third study, we compared different vaccine strategies modulating vaccine doses and injection times in healthy volunteers but also in a mouse model of hyporesponsiveness developed in our laboratory. Our hypothesis was that modulation of the vaccine schedule using both vaccines could both induce long-term protection and prevent hyporesponsiveness. Our results showed that decreased doses of PPV23 or concomitant injection of both vaccines did not prevent hyporesponsiveness. However, by increasing the delay between PCV13 and PPV23, the phenomenon of hyporesponsiveness is limited. Clinical studies in patients at risk of IPD are needed to evaluate a delayed combined strategy, where PPV23 would be received at least 6 to 12 months after PCV13.Deux vaccins sont actuellement disponibles pour la prévention des infections invasives à pneumocoques (IIP) : un vaccin polysaccharidique Pneumovax® (PPV23) et un vaccin conjugué Prevenar13® (PCV13), induisant respectivement une protection contre 23 et 13 sérotypes. Le PPV23 est considéré comme faiblement immunogène, en particulier chez les personnes âgées et les patients immunodéprimés. Le PCV13, en revanche, en raison de la conjugaison à une protéine porteuse, présente l'avantage d'induire une réponse immunitaire T-dépendante, non observée avec le vaccin PPV23. Dans notre travail nous avons donc évalué l'impact des stratégies vaccinales utilisant le PCV13 et le PPV23 sur différentes populations de patients à risque. Dans une première étude, nos résultats sur la vaccination anti-pneumococcique chez des patients atteints de myélome indolent (SMM) ont montré qu'une dose de PCV13 seul, induisait une réponse immune transitoire et de faible persistance. Ces résultats suggéraient l'utilisation d'un schéma vaccinal incluant plusieurs doses de PCV13 ou une association avec le PPV23. Depuis 2013, ce schéma combiné du PCV13 et du PPV23 est le schéma recommandé par la Haute Autorité de Santé en France chez les patients à risque, avec les délais suivants : une dose de PCV13 suivie d'une dose de PPV23, 8 semaines après. Nous avons par la suite étudié cette stratégie vaccinale combinée chez des patients à risque d'IIP : patients atteints de lupus érythémateux systémique (SLE) et patients atteints de polyarthrite rhumatoïde (PR). Nos résultats montrent une immunogénicité à court terme de la stratégie combinée, mais une protection qui ne persiste pas au-delà de deux ans. De façon surprenante, les taux d'anticorps 2 ans après la vaccination, sont inférieurs aux taux pré-vaccinaux pour les patients PR. Cet effet délétère du PPV23 sur la réponse vaccinale induite par le PCV13 est appelé hyporéponse. Ce phénomène, observé chez les patients PR, ne se retrouve pas chez les patients SLE dont la vaccination PPV23 a été effectuée plus à distance du PCV13. Ces résultats suggèrent que le schéma vaccinal plus tardif (c'est-à-dire une vaccination par le PPV23 six mois après le PCV13 au lieu de deux mois) inhiberait le phénomène d'hyporéponse. Dans une troisième partie, nous avons comparé différents schéma vaccinaux modulant les doses des vaccins et les délais d'injection chez des volontaires sains mais également dans un modèle murin d'hyporéponse développé au sein du laboratoire. Notre hypothèse était que la modulation du schéma vaccinal utilisant les 2 vaccins pouvait à la fois induire une protection à long terme et prévenir l'hyporéponse. Nos résultats ont montré que l'utilisation d'une dose diminuée de PPV23 ou l'injection concomitante des deux vaccins n'empêchaient pas l'hyporéponse. En revanche, en allongeant le délai entre le PCV13 et le PPV23, le phénomène d'hyporéponse est limité. Des études cliniques chez les patients à risque d'IIP sont nécessaires afin d'évaluer une stratégie combinée tardive, où le PPV23 serait reçu au moins 6 à 12 mois après le PCV13

Anti-pneumococcal vaccines in patients at risk of invasive pneumococcal disease and prevention of hyporesponsiveness

Deux vaccins sont actuellement disponibles pour la prévention des infections invasives à pneumocoques (IIP) : un vaccin polysaccharidique Pneumovax® (PPV23) et un vaccin conjugué Prevenar13® (PCV13), induisant respectivement une protection contre 23 et 13 sérotypes. Le PPV23 est considéré comme faiblement immunogène, en particulier chez les personnes âgées et les patients immunodéprimés. Le PCV13, en revanche, en raison de la conjugaison à une protéine porteuse, présente l'avantage d'induire une réponse immunitaire T-dépendante, non observée avec le vaccin PPV23. Dans notre travail nous avons donc évalué l'impact des stratégies vaccinales utilisant le PCV13 et le PPV23 sur différentes populations de patients à risque. Dans une première étude, nos résultats sur la vaccination anti-pneumococcique chez des patients atteints de myélome indolent (SMM) ont montré qu'une dose de PCV13 seul, induisait une réponse immune transitoire et de faible persistance. Ces résultats suggéraient l'utilisation d'un schéma vaccinal incluant plusieurs doses de PCV13 ou une association avec le PPV23. Depuis 2013, ce schéma combiné du PCV13 et du PPV23 est le schéma recommandé par la Haute Autorité de Santé en France chez les patients à risque, avec les délais suivants : une dose de PCV13 suivie d'une dose de PPV23, 8 semaines après. Nous avons par la suite étudié cette stratégie vaccinale combinée chez des patients à risque d'IIP : patients atteints de lupus érythémateux systémique (SLE) et patients atteints de polyarthrite rhumatoïde (PR). Nos résultats montrent une immunogénicité à court terme de la stratégie combinée, mais une protection qui ne persiste pas au-delà de deux ans. De façon surprenante, les taux d'anticorps 2 ans après la vaccination, sont inférieurs aux taux pré-vaccinaux pour les patients PR. Cet effet délétère du PPV23 sur la réponse vaccinale induite par le PCV13 est appelé hyporéponse. Ce phénomène, observé chez les patients PR, ne se retrouve pas chez les patients SLE dont la vaccination PPV23 a été effectuée plus à distance du PCV13. Ces résultats suggèrent que le schéma vaccinal plus tardif (c'est-à-dire une vaccination par le PPV23 six mois après le PCV13 au lieu de deux mois) inhiberait le phénomène d'hyporéponse. Dans une troisième partie, nous avons comparé différents schéma vaccinaux modulant les doses des vaccins et les délais d'injection chez des volontaires sains mais également dans un modèle murin d'hyporéponse développé au sein du laboratoire. Notre hypothèse était que la modulation du schéma vaccinal utilisant les 2 vaccins pouvait à la fois induire une protection à long terme et prévenir l'hyporéponse. Nos résultats ont montré que l'utilisation d'une dose diminuée de PPV23 ou l'injection concomitante des deux vaccins n'empêchaient pas l'hyporéponse. En revanche, en allongeant le délai entre le PCV13 et le PPV23, le phénomène d'hyporéponse est limité. Des études cliniques chez les patients à risque d'IIP sont nécessaires afin d'évaluer une stratégie combinée tardive, où le PPV23 serait reçu au moins 6 à 12 mois après le PCV13.Two vaccines are currently available for the prevention of invasive pneumococcal diseases (IPD): a polysaccharide vaccine, Pneumovax® (PPV23) and a conjugate vaccine, Prevenar13® (PCV13), inducing protection against 23 and 13 serotypes, respectively. PPV23 is considered to be weakly immunogenic, particularly in the elderly and immunocompromised patients. PCV13, however, due to the conjugation to a carrier protein, has the advantage of inducing a T-dependent immune response, not observed with PPV23 vaccine. In our work, we therefore evaluated the impact of vaccine strategies using PCV13 and PPV23 on different populations of patients at risk of IPD. In a first study, our results on anti-pneumococcal vaccination in patients with smoldering myeloma (SMM) showed that a single dose of PCV13 induces a transient immune response and long term persistence. These results suggested the use of a vaccination schedule including several doses of PCV13 or association with the PPV23. Since 2013, this combined strategy of PCV13 and PPV23 is recommended by la Haute Autorité de Santé (HAS) for patients at risk, with the following delays: a dose of PCV13 followed by a dose of PPV23, 8 weeks later. We then studied this combined vaccine strategy in patients at risk of IPD: patients with systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). Our results show a short-term immunogenicity of the combined strategy, but a protection that does not persist beyond two years. Surprisingly, antibody levels 2 years after vaccination are lower than pre-vaccine levels for RA patients. This negative effect of PPV23 on PCV13-induced immune response is called hyporesponsiveness. This phenomenon, observed in RA patients, is not found in SLE patients who received PPV23 vaccination at distance from PCV13. These results suggest that the delayed vaccination schedule (ie, PPV23 vaccination six months after PCV13 instead of two months) could inhibit the hyporesponsiveness phenomenon. In a third study, we compared different vaccine strategies modulating vaccine doses and injection times in healthy volunteers but also in a mouse model of hyporesponsiveness developed in our laboratory. Our hypothesis was that modulation of the vaccine schedule using both vaccines could both induce long-term protection and prevent hyporesponsiveness. Our results showed that decreased doses of PPV23 or concomitant injection of both vaccines did not prevent hyporesponsiveness. However, by increasing the delay between PCV13 and PPV23, the phenomenon of hyporesponsiveness is limited. Clinical studies in patients at risk of IPD are needed to evaluate a delayed combined strategy, where PPV23 would be received at least 6 to 12 months after PCV13

Immunogenicity and persistence of a prime-boost re-vaccination strategy for pneumococcal vaccines in patients with rheumatoid arthritis

Objectives: Patients with rheumatoid arthritis (RA) are at an increased risk of Pneumococcal infections. Immunogenicity and persistence of a prime-boost revaccination strategy using 13-valent/23-valent anti-pneumococcal vaccines was evaluated in patients with RA treated by Methotrexate (MTX) and anti-TNF. Method: Twenty-four patients with RA received one dose of PCV13 (Prevenar13®; Pfizer) followed two months later by one dose of PPV23 (Pneumovax®, Merck). Concentrations of IgG specific for 7 serotypes common to both vaccines and 3 uncommon serotypes, included only in the PPV23 were measured by ELISA and Opsonophagocytic Assay (OPA) at baseline and after 4, 12 and 24 months post-vaccine. Results: Similar percentages of protection were found at 4 months (63% vs. 55%), 12 months (54% vs. 50%) and 24 months (52% vs. 55%) for the 7 common and 3 uncommon serotypes when antibody titers were assayed by ELISA. Based on functional antibody measurements by OPA, a decrease of protected patients was observed 24 months after vaccine with only 19% of patients protected compared to 29% at baseline. Conclusion: Although the combined pneumococcal revaccination strategy induces good protection in the short term in RA patients, this protection does not persist beyond two years with levels of functional antibody decreasing below pre-vaccine levels. We did not observe a higher efficacy of the conjugate vaccine compared to the polysaccharide vaccine. Our results clearly question the advantage of the prime-boost strategy as it highlight the possible hyporesponse induced by PPV23 against the immune response elicited by the primo-injection of the PCV13 vaccine

Immunogenicity and persistence of the 13-valent Pneumococcal Conjugate Vaccine (PCV13) in patients with untreated Smoldering Multiple Myeloma (SMM): A pilot study

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that frequently progress to multiple myeloma (MM), a disease at high risk of pneumococcal infections. Moreover, if the polysaccharide vaccine is poorly immunogenic in MM, the 13-valent conjugated vaccine has never been tested in clonal plasma cell disorders. We evaluated its immunogenicity for 7 serotypes in 20 patients ≥ 50 years of age with smoldering multiple myeloma (SMM) pre and post routine-vaccination with PCV13.Concentrations of IgG specific for 7 serotypes were measured at baseline, 1, 6, and 12 months after vaccination by standardized ELISA and an Opsonophagocytic Assay (OPA). The primary endpoint was the proportion of patients responding to at least 5 of the 7 serotypes by ELISA at one month.At 1 month post vaccination, 12 patients (60%) were responders by ELISA, among whom 8 were also responders by OPA. At 6 months, 6 (30% of total) of the 12 responders had persistent immunity, and only 2 (10% of total) at 12 months. These results suggested a partial response in this population and a rapid decrease in antibody levels in the first months of vaccination.Although one injection of the 13-valent pneumococcal conjugate vaccine is immunogenic in some patients with SMM, the response is transient. Repeated injections are likely to be needed for effective and sustained protection

Serum IgG2 levels predict long-term protection following pneumococcal vaccination in systemic lupus erythematosus (SLE)

International audienceSystemic lupus erythematosus (SLE) patients are at risk for pneumococcal infection. Twenty-one consecutive SLE patients (40[25-75] years) received the sequential PCV13/PPSV23 vaccine and factors associated with long-term protection were analyzed. Immune protection, defined by an antigen-specific IgG concentration ≥1.3 µg/mL for at least 70% of 7 pneumococcal serotypes was assessed at baseline, 2, 6, 12 and 36 months defining long-term protection. Only 10 patients showed pneumococcal immune protection 36 months after vaccination. Eleven (52.4%) patients had no long-term protection with a seroconversion that never or only transiently occurred. SLE disease features, treatment received and immunological characteristics did not differ between protected and unprotected patients except for the pre-vaccination IgG2 serum levels. Serum IgG2 level >2.125 µg/ml showed a sensitivity of 100% and a specificity of 90.9% for long-term protection. Sequential pneumococcal vaccination conferred poor immune protection in SLE. Baseline IgG2 serum level identified patients able to benefit from pneumococcal vaccination

Pneumococcal vaccination in patients with systemic lupus erythematosus: A multicenter placebo-controlled randomized double-blind study

International audienceBackground: Invasive pneumococcal disease and respiratory tract infections are both frequent and severe in patients with systemic lupus erythematosus (SLE). This study aimed to compare the immunological efficacy and safety of pneumococcal vaccination with the 23-valent polysaccharide (PPS) vaccine alone to a sequential immunization with the 7-valent pneumococcal conjugate (PnCj) vaccine followed by PPS in patients with SLE and stable diseaase.Methods: Multicenter randomized placebo-controlled double-blind trial: PPS vaccine alone (placebo-PPS group) or PnCj vaccine followed by PPS vaccine (PnCj-PPS group) 24weeks later. The primary endpoint was the rate of responders at week 28 to at least 5 of the 7 serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) shared by both PPS and PnCj. Pneumococcal IgG antibodies' opsonophagocytic activity (OPA) were also assessed.Results: Twenty-five patients in the placebo-PPS group and 17 in the PnCj-PPS group were included in a modified intention-to-treat analysis. The primary endpoint was reached in 72% (18/25) in the placebo-PPS and 76% (13/17) in the PnCj-PPS group (p=0.75). There was no difference in the rates of responders with OPA. At week 52, 13/18 (72%) patients in the placebo-PPS group and 10/13 (77%) patients in the PnCj-PPS group (p=0.77) that met the primary endpoint at week 28 were still responders to ≥5/7 serotypes shared by both PPS and PnCj vaccines. Nine SLE flares were reported in 6 patients (4 in the placebo-PPS and 2 in the PnCj-PPS groups respectively, p=0.70).Conclusion: Sequential administration of PnCj vaccine followed by PPS vaccine is safe and shows short-term immunological efficacy in patients with SLE but was not superior to the PPS vaccine alone.Trial registration: www.clinicaltrials.gov, NCT NCT00611663

T-independent responses to polysaccharides in humans mobilize marginal zone B cells prediversified against gut bacterial antigens

Marginal zone (MZ) B cells are one of the main actors of T-independent (TI) responses in mice. To identify the B cell subset(s) involved in such responses in humans, we vaccinated healthy individuals with Pneumovax, a model TI vaccine. By high-throughput repertoire sequencing of plasma cells (PCs) isolated 7 days after vaccination and of different B cell subpopulations before and after vaccination, we show that the PC response mobilizes large clones systematically, including an immunoglobulin M component, whose diversification and amplification predated the pneumococcal vaccination. These clones could be mainly traced back to MZ B cells, together with clonally related IgA+ and, to a lesser extent, IgG+CD27+ B cells. Recombinant monoclonal antibodies isolated from large PC clones recognized a wide array of bacterial species from the gut flora, indicating that TI responses in humans largely mobilize MZ and switched B cells that most likely prediversified during mucosal immune responses against bacterial antigens and acquired pneumococcal cross-reactivity through somatic hypermutation

T-independent responses to polysaccharides in humans mobilize marginal zone B cells prediversified against gut bacterial antigens

Marginal zone (MZ) B cells are one of the main actors of T-independent (TI) responses in mice. To identify the B cell subset(s) involved in such responses in humans, we vaccinated healthy individuals with Pneumovax, a model TI vaccine. By high-throughput repertoire sequencing of plasma cells (PCs) isolated 7 days after vaccination and of different B cell subpopulations before and after vaccination, we show that the PC response mobilizes large clones systematically, including an immunoglobulin M component, whose diversification and amplification predated the pneumococcal vaccination. These clones could be mainly traced back to MZ B cells, together with clonally related IgA+ and, to a lesser extent, IgG+CD27+ B cells. Recombinant monoclonal antibodies isolated from large PC clones recognized a wide array of bacterial species from the gut flora, indicating that TI responses in humans largely mobilize MZ and switched B cells that most likely prediversified during mucosal immune responses against bacterial antigens and acquired pneumococcal cross-reactivity through somatic hypermutation

Am J Trop Med Hyg

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