Preclinical evaluation of an investigational 21-valent pneumococcal conjugate vaccine,V116, in adult-rhesus monkey,rabbit, and mouse models

Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116, an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV), containing pneumococcal polysaccharides (PnPs) 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, and a de-O-acetylated 15B (deOAc15B) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 in adult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.     

A phase 3, randomized,controlled, open-label study to evaluate the persistence up to 5 years of 1 or 2 doses of meningococcal conjugate vaccine MenACWY-TT given with or without 13-valent pneumococcal conjugate vaccine in 12–14-month-old children

BackgroundImmunogenicity and safety up to 5 years after administration of 1 or 2 doses of quadrivalent meningococcal serogroup A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) given alone or with 13-valent pneumococcal conjugate vaccine (PCV13) in children was investigated.MethodsThis phase 3 study randomized healthy 12–24-month-olds to MenACWY-TT at Month 0 (ACWY1d), MenACWY-TT at Months 0 and 2 (ACWY2d), MenACWY-TT and PCV13 at Month 0 (Co-Ad), or PCV13 at Month 0 and MenACWY-TT at Month 2 (PCV13/ACWY). Immune responses 1, 3, and 5 years after primary vaccination were evaluated with serum bactericidal activity using rabbit complement (rSBA) titers ≥ 1:8 and geometric mean titers (GMTs). Evaluation of serious adverse events up to 5 years after primary vaccination are reported.ResultsOf the 802 children randomized in the study, 619 completed the study through Year 5. Immune responses after vaccination declined over time but were higher 5 years after vaccination compared with levels before vaccination. At Year 5, the percentages of children with rSBA titers ≥ 1:8 across all serogroups were 20.5 %?58.6 %, 28.4 %?65.8 %, 23.9 %?52.8 %, and 19.4 %?55.8 % in the ACWY1d, ACWY2d, Co-Ad, and PCV13/ACWY groups, respectively. Comparable antibody persistence at Year 5 was observed for participants receiving 1 or 2 doses of MenACWY-TT, although GMTs were elevated in those who received 2 versus 1 dose. The percentage of children with protective antibody titers at Year 5 was similar in participants who received PCV13 and MenACWY-TT compared with that observed for participants who only received 1 or 2 MenACWY-TT doses. No new safety concerns were identified during the study period.ConclusionAntibody responses persisted in the majority of children up to 5 years after primary vaccination with MenACWY-TT administered in a 1- or 2-dose regimen with or without PCV13, with no new safety concerns identified.ClinicalTrials.gov Identifier NCT01939158; EudraCT number 2013–001083-28.     

Delayed Leukoreduction of whole blood with a platelet-sparing filter to increase low-titer group O whole blood production in the United States

Background

Demand for low-titer Group O whole blood (LTOWB) is increasing for trauma. The whole blood (WB) platelet-sparing (WB-SP) filter enables leukoreduction (LR) while retaining platelet quantity and function; however, in the United States WB must be filtered and placed in the cold within 8 h of collection. A longer processing window would facilitate improved logistics and supply of LR-WB to meet the growing medical need. This study evaluated the impact of increasing filtration timing from <8 h to <12 h on the quality of LR-WB.

Study Design and Methods

Thirty WB units were collected from healthy donors. Control units were filtered within 8 h and test units within 12 h of collection. WB was tested throughout 21 days of storage. Hemolysis, WBC content, component recovery, and 25 additional markers of WB quality were tested including hematologic and metabolic markers, RBC morphology, aggregometry, thromboelastography, and p-selectin.

Results

There were 0 failures for residual WBC content, hemolysis, or pH, and no differences in component recovery between arms. Few differences in metabolic parameters were observed, but the small effect size suggests these are not clinically significant. Trends throughout storage were similar and filtration timing did not impact hematological parameters, platelet activation and aggregation, or hemostatic capacity.

Conclusion

Our studies showed that extending filtration timing from 8 to 12 h from the collection does not significantly impact the quality of LR-WB. Characterization of the platelets demonstrated that storage lesions were not exacerbated. Extending the time from collection to filtration will improve LTOWB inventory in the United States.     

Long-term transition of antibody titers in healthcare workers following the first to fourth doses of mRNA COVID-19 vaccine: Comparison of two automated SARS-CoV-2 immunoassays

Anti-spike receptor binding domain (S-RBD) antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which best correlates with virus-neutralizing antibody is useful for estimating the period of protection and identifying the timing of additional booster doses. Long-term transition of the S-RBD antibody titer and the antibody responses among healthy individuals remain unclear. In the present study, therefore, we monitored the S-RBD antibody titers of 16 healthcare workers every 4 weeks for 76 weeks after vaccination with a fourth dose of mRNA-1273 (Moderna) following three doses of BNT162b2 (Pfizer/BioNTech) using two commercial automated immunoassays (Roche and Abbott). Two antibody responses to the vaccine were similar with an up-down change before and after the second (weeks 3), third (weeks 40) and fourth (week 72) vaccinations, but the titer did not fall below the assay's positivity threshold in any individual. The peak level of the geometric mean titer (GMT) in the Roche assay was highest after the third vaccination, and that in Abbott assay was highest after the fourth vaccination but almost equal to that after the third vaccination. Both the geometric mean fold rise (GMFR) demonstrated by the Roche and Abbott assays were highest after the third vaccination. Antibody titers determined by the Roche and Abbott assays showed a positive strong correlation (correlation coefficient: 0.70 to 0.99), but the ratio (Roche/Abbott) of antibodies demonstrated by both assays increased 0.46- to 8.26-fold between weeks 3 and 76. These findings will be helpful for clinicians when interpreting results for SARS-CoV-2 antibody levels and considering future vaccination strategies.