Potential serotype-specific effectiveness against IPD of pneumococcal conjugate vaccines V114 and PCV20 in children given a 2+1 dosing regimen.

BACKGROUND: Next generation, higher valency pneumococcal conjugate vaccines (PCVs) are assessed and licensed by comparing the immune response across serotypes shared with the PCVs that are standard of care for prevention of pneumococcal disease. METHODS: Using a previously qualified method we predicted the serotype-specific vaccine effectiveness (VE) against invasive pneumococcal disease of V114 and PCV20 for the serotypes shared with PCV13 in an EU, Russian, and Australian pediatric population that is recommended to receive a 2 + 1 dosing regimen. RESULTS: The estimated protective antibody concentrations ranged from 0.03 (serotype 23F) to 1.49 µg/mL (serotype 19F). Predicted VE values for V114 ranged from 79% (serotype 5) to 100% (serotype 23F). V114 had comparable effectiveness to PCV13 for all but one of shared serotypes, with predicted higher effectiveness (in V114) against serotype 3 (93% vs. 65%). Predicted VE values for PCV20 ranged from 47% (serotype 3) to 91% (serotype 14). PCV20 predicted VE was lower than PCV13's for serotypes 4, 19F, 23F, 1, 3, 5, 6A, 7F, and 19A. CONCLUSIONS: Predicted serotype-specific VE values suggest that, with a 2 + 1 dosing regimen, V114 will have greater effectiveness than PCV20 against PCV13 serotypes, particularly for the still-prevalent serotype 3. Real-world VE studies will ultimately provide clarity on the effectiveness of novel PCVs and support further confidence in and/or improvements to modeling efforts.

Pediatric pneumococcal conjugate vaccines (PCVs) were first introduced in Europe in the early 2000s and their incorporation into national immunization programs has helped decrease the incidence of invasive pneumococcal disease (IPD) in Europe and globally. However, some IPD persists, due both to the emergence of non-vaccine pneumococcal serotypes and to the persistence of certain vaccine-targeted serotypes. Higher valency vaccines have been developed to help prevent IPD arising from these serotypes. The goal of the present study is to employ a previously developed model to predict the serotype-specific vaccine effectiveness of higher valency PCVs in a pediatric population that is recommended to receive a 2 + 1 dosing schedule.

Predicted serotype-specific effectiveness of pneumococcal conjugate vaccines V114 and PCV20 against invasive pneumococcal disease in children.

BACKGROUND: Next-generation, higher-valency pneumococcal conjugate vaccines (PCVs), 15-valent PCV V114 and 20-valent PCV (PCV20), have been assessed by comparing their immune responses across serotypes shared with the 13-valent PCV (PCV13). Without efficacy or real-world vaccine effectiveness (VE) it becomes important to relate IgG titers to VE to aid in the interpretation of the immune response elicited by V114 and PCV20. METHODS: We estimated the protective antibody concentrations for each serotype in 7-valent PCV (PCV7) and PCV13 which were then used to predict the serotype-specific VE for each PCV7 and PCV13 non PCV7 serotype present in V114 and PCV20. RESULTS: The predicted effectiveness of V114 was comparable to PCV7 and PCV13 for 11 of the 13 shared serotypes (1, 4, 5, 6B, 7F, 9 V, 14, 18C, 19A, 19F, and 23F), with improved effectiveness against serotype 3 and decreased effectiveness against serotype 6A. PCV20 had predicted effectiveness comparable to PCV7 and PCV13 for 7 of the 13 shared serotypes (5, 6A, 7F, 9 V, 18C, 19F, and 23F), with decreased effectiveness against the remaining serotypes (1, 3, 4, 6B, 14, and 19A). CONCLUSIONS: Prediction of serotype-specific VE values suggests that V114 retains greater effectiveness than PCV20 toward most serotypes present in PCV7 and PCV13.

Pediatric pneumococcal conjugate vaccines (PCVs) first became available in 2000, when the seven-valent PCV (PCV7) was approved. Since then, PCV7 has been replaced by higher-valency vaccines, including the ten-valent (PCV10) and thirteen-valent (PCV13) vaccines and, more recently, fifteen- and twenty-valent vaccines (V114 and PCV20, respectively). The increase in valency provides broader serotype coverage against invasive pneumococcal disease (IPD) in children. However, IPD due to serotypes contained in PCV7 and PCV13 continue to be observed. In the current study, we used a previously published method to estimate the vaccine effectiveness of V114 and PCV20 in a US and Puerto Rican pediatric population that is recommended to receive a 3 + 1 dosing schedule.

Predicting vaccine effectiveness against invasive pneumococcal disease in children using immunogenicity data.

The strength of the immune response, as measured by antibody concentrations, varies between pneumococcal conjugate vaccines (PCVs). Linking immunogenicity and effectiveness is necessary to assess whether changes in immune response from currently recommended PCVs to next-generation vaccines could impact effectiveness. Simulated reverse cumulative distribution curves were generated using published serotype-specific IgG concentrations with placebo or PCV7. This was combined with the published estimates of serotype-specific vaccine effectiveness of PCV7 against invasive pneumococcal disease to estimate the protective antibody concentration for each serotype in PCV7. Then, based on the published serotype-specific IgG concentrations in PCV13 recipients, reverse cumulative distribution curves were generated for the serotypes shared between PCV13 and PCV7. These estimated protective antibody concentration values were then used to predict the vaccine effectiveness of PCV13. The results were compared to published aggregate values for vaccine effectiveness. The aggregate median predicted vaccine effectiveness values were similar to previously reported observed values for the United Kingdom (93% versus 90%), Australia (71% versus 70%), and Germany (91% versus 90%). These results demonstrate that IgG concentrations of next-generation PCVs can be used to generate reliable estimates of vaccine effectiveness for serotypes shared with established PCVs.

Predicting effectiveness of the V114 vaccine against invasive pneumococcal disease in children.

BACKGROUND: The potential impact of new pneumococcal conjugate vaccines (PCVs) is assessed by using immune responses to predict their effectiveness against invasive pneumococcal disease (IPD). This analysis predicted the serotype-specific effectiveness against IPD of a new 15-valent PCV (V114) for the serotypes shared with a 13-valent PCV (PCV13), in a US pediatric population given a 3 + 1 dosing regimen. METHODS: Beginning with the known serotype-specific antibody concentrations after vaccination with placebo, 7-valent PCV (PCV7) and PCV13, reverse cumulative distribution curves were used, along with published serotype-specific vaccine effectiveness of PCV7 and PCV13, to derive a protective antibody concentration (Cp) for each PCV13 serotype in V114. Serotype-specific effectiveness was predicted using the Cp estimates and the respective serotype-specific antibody concentrations of placebo and V114 recipients in recent pediatric clinical trials. RESULTS: Predicted serotype-specific V114 effectiveness values ranged from 86% to 99% for PCV7 serotypes and from 59% to 97% for (non-PCV7) PCV13 serotypes. CONCLUSIONS: V114 serotype-specific effectiveness against IPD in a US pediatric population was predicted to be largely comparable to that of PCV7 and PCV13 for shared serotypes, with models suggesting likelihood of high overall benefit gained from increased serotype 3 effectiveness, and additional protection against serotypes 22 F and 33 F.

Comparison of Titer and Signal to Noise (S/N) for Determination of Anti-drug Antibody Magnitude Using Clinical Data from an Industry Consortium.

During biotherapeutic drug development, immunogenicity is evaluated by measuring anti-drug antibodies (ADAs). The presence and magnitude of ADA responses is assessed using a multi-tier workflow where samples are screened, confirmed, and titered. Recent reports suggest that the assay signal to noise ratio (S/N) obtained during the screening tier correlates well with titer. To determine whether S/N could more broadly replace titer, anonymized ADA data from a consortium of sponsors was collected and analyzed. Datasets from clinical programs with therapeutics of varying immunogenicity risk levels (low to high), common ADA assay platforms (ELISA and MSD) and formats (bridging, direct, solid-phase extraction with acid dissociation), and titration approaches (endpoint and interpolated) were included in the analysis. A statistically significant correlation between S/N and titer was observed in all datasets, with a strong correlation (Spearman's r > 0.8) in 11 out of 15 assays (73%). For assays with available data, conclusions regarding ADA impact on pharmacokinetics and pharmacodynamics were similar using S/N or titer. Subject ADA kinetic profiles were also comparable using the two measurements. Determination of antibody boosting in patients with pre-existing responses could be accomplished using similar approaches for titer and S/N. Investigation of factors that impacted the accuracy of ADA magnitude measurements revealed advantages and disadvantages to both approaches. In general, S/N had superior precision and ability to detect potentially low affinity/avidity responses compared to titer. This analysis indicates that S/N could serve as an equivalent and in some cases preferable alternative to titer for assessing ADA magnitude and evaluation of impact on clinical responses.

Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis.

The lengthy treatment time for tuberculosis (TB) is a primary cause for the emergence of multidrug resistant tuberculosis (MDR-TB). One approach to improve TB therapy is to develop an inhalational TB therapy that when administered in combination with oral TB drugs eases and shortens treatment. Spectinamides are new semisynthetic analogues of spectinomycin with excellent activity against Mycobacterium tuberculosis (Mtb), including MDR and XDR Mtb strains. Spectinamide-1599 was chosen as a promising candidate for development of inhalational therapy. Using the murine TB model and intrapulmonary aerosol delivery of spectinamide-1599, we characterized the pharmacokinetics and efficacy of this therapy in BALB/c and C3HeB/FeJ mice infected with the Mtb Erdman strain. As expected, spectinamide-1599 exhibited dose-dependent exposure in plasma, lungs, and ELF, but exposure ratios between lung and plasma were 12-40 times higher for intrapulmonary compared to intravenous or subcutaneous administration. In chronically infected BALB/c mice, low doses (10 mg/kg) of spectinamide-1599 when administered thrice weekly for two months provide efficacy similar to that of higher doses (50-100 mg/kg) after one month of therapy. In the C3HeB/FeJ TB model, intrapulmonary aerosol delivery of spectinamide-1599 (50 mg/kg) or oral pyrazinamide (150 mg/kg) had limited or no efficacy in monotherapy, but when both drugs were given in combination, a synergistic effect with superior bacterial reduction of >1.8 log10 CFU was observed. Throughout the up to eight-week treatment period, intrapulmonary therapy was well-tolerated without any overt toxicity. Overall, these results strongly support the further development of intrapulmonary spectinamide-1599 as a combination partner for anti-TB therapy.

Pharmacokinetics of Monoclonal Antibodies.

Monoclonal antibodies (mAbs) have developed in the last two decades into the backbone of pharmacotherapeutic interventions in a variety of indications, with currently more than 40 mAbs approved by the US Food and Drug Administration, and several dozens more in clinical development. This tutorial will review major drug disposition processes relevant for mAbs, and will highlight product-specific and patient-specific factors that modulate their pharmacokinetic (PK) behavior and need to be considered for successful clinical therapy.

Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity-Mediated Impact on Therapeutic Exposure.

In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co-administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies. Three groups of Sprague Dawley rats (n = 18) were treated with low (0.01 mg/kg), moderate (50 mg/kg), or high (300 mg/kg) doses of mAb1. Experimental groups also received either methotrexate or tacrolimus/sirolimus immune suppressive regimens. ELISA-based methods were utilized to measure and characterize ADA and mAb1 pharmacokinetics (PK). Results demonstrated a stepwise increase in immunogenicity with mAb1 dosage. Methotrexate significantly lowered incidence of anti-variable region antibodies at moderate mAb1 dose (P < 0.05), while tacrolimus/sirolimus did likewise at moderate and high doses (P < 0.01) of mAb1. Except for low-dose mAb1 + methotrexate, all immunosuppressed groups displayed more than a 70-fold decrease in ADA magnitude (P < 0.05). This abrogation in ADA response correlated with more mAb1 in circulation by week 4 for moderate- and high-dosed mAb1 groups. These data provide an approach to mitigate preclinical immunogenicity by the use of immunosuppressant regimens. Such preconditioning can support preclinical drug development of human therapeutics that are antigenic to animals. Similar approaches could be investigated for wider application to novel therapeutics.

Pharmacokinetics of ponazuril after oral administration to healthy llamas (Lama glama).

OBJECTIVE: To determine the pharmacokinetics after oral administration of a single dose of ponazuril to healthy llamas. ANIMALS: 6 healthy adult llamas. PROCEDURES: Ponazuril (20 mg/kg) was administered once orally to 6 llamas (day 0). Blood samples were obtained on days 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 14, 21, 28, 35, 42, and 49. Serum ponazuril concentrations were determined by use of a validated reverse-phase high-performance liquid chromatography assay with UV absorbance detection. Pharmacokinetic parameters were derived by use of a standard noncompartmental pharmacokinetic analysis. RESULTS: Mean ± SD area under the serum concentration-time curve was 7,516 ± 2,750 h•mg/L, maximum serum ponazuril concentration was 23.6 ± 6.0 mg/L, and the elimination half-life was 135.5 ± 16.7 hours. Serum concentration of ponazuril peaked at 84 hours (range, 48 to 120 hours) after administration and gradually decreased but remained detectable for up to 35 days after administration. No adverse effects were observed during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: The rate and extent of absorption following oral administration of a single dose of ponazuril were sufficient to result in potentially effective concentrations, and the drug was tolerated well by llamas. At this dose, ponazuril resulted in serum concentrations that were high enough to be effective against various Apicomplexans on the basis of data for other species. The effective ponazuril concentration that will induce 50% inhibition of parasite growth for Eimeria macusaniensis in camelids is currently unknown.