Safety and immunogenicity of a multivalent pneumococcal conjugate vaccine given with 13-valent pneumococcal conjugate vaccine in healthy infants: A phase 2 randomized trial.

Use of pneumococcal conjugate vaccines (PCVs) has led to substantial reductions in the global burden of pediatric pneumococcal disease. Expansion of serotype coverage has been achieved by increasing PCV valency, but this may carry the potential risk of antibody interference. A complementary 7-valent PCV (cPCV7) including polysaccharide conjugates from 7 non-13-valent (PCV13) serotypes was developed to potentially complement PCV13-mediated protection and expand serotype coverage. This study evaluated cPCV7 and PCV13 coadministered in separate limbs or separated in time in infants. This phase 2, multicenter, open-label study included 512 infants randomized 1:1:1 to receive cPCV7 coadministered with PCV13 at ages 2, 4, 6, and 12 months (cPCV7 Coadministered); cPCV7 given at ages 3, 5, 7, and 13 months, 3‒5 weeks after PCV13 (cPCV7 Separated); or PCV13 at ages 2, 4, 6, and 12 months followed by a single supplemental dose of cPCV7 at 13 months (PCV13 Control). Safety evaluations included local reactions, systemic events, and adverse events. Serotype-specific immunoglobulin G concentrations and opsonophagocytic activity titers were assessed. The safety profile of cPCV7 was similar to that of PCV13. cPCV7 was well-tolerated in infants when coadministered with or given separately from PCV13. Robust and functional immune responses for all cPCV7 serotypes were observed in both cPCV7 groups. No immunologic interference was observed for either the cPCV7 or PCV13 serotypes with coadministration. A single cPCV7 dose induced immune responses in toddlers. These findings support potential coadministration of a complementary PCV to supplement protection provided by existing PCVs.Trial registration: ClinicalTrials.gov, NCT03550313.

A phase 3 study evaluating the lot consistency, immunogenicity, safety, and tolerability of a Clostridioides difficile vaccine in healthy adults 65 to 85 years of age.

BACKGROUND: A toxoid-based Clostridioides difficile vaccine is currently in development. Here, we report lot-to-lot consistency, immunogenicity, safety, and tolerability of 3 C difficile vaccine doses in healthy older adults. METHODS: This phase 3, placebo-controlled study randomized (1:1:1:1) healthy adults 65 to 85 years of age to 1 of 3 C difficile vaccine lots or placebo. Participants received C difficile vaccine (200 µg total toxoid) or placebo (Months 0, 1, 6). The primary immunogenicity objective was lot-to-lot consistency (2-sided 95 % CIs within 0.5 and 2 for comparisons of geometric mean concentration [GMC] ratios) for toxins A- and B-specific neutralizing antibody levels 1 month after Dose 3. Safety outcomes included local reactions and systemic events ≤7 days after vaccination, adverse events (AEs), and serious AEs (SAEs). RESULTS: Of 1317 enrolled participants, 1218 completed the study. C difficile vaccine immunogenicity was consistent across lots, with neutralizing antibody responses 1 month after Dose 3 for both toxin A (GMC [95 % CI]: lot 1, 878.8 [786.3, 982.2]; lot 2, 873.0 [779.2, 978.1]; lot 3, 872.9 [782.6, 973.5]) and toxin B (lot 1, 5823.9 [5041.0, 6728.4]; lot 2, 5462.8 [4733.4, 6304.7]; lot 3, 5426.0 [4724.4, 6231.8]). Two-sided 95 % CIs for GMC ratios were within 0.5 and 2 for toxins A and B, indicating lot-to-lot consistency was achieved. C difficile vaccine was well tolerated, with similar rates of local reactions and systemic events among vaccine lots. AE and SAE rates were similar across C difficile vaccine (36.5 % and 4.5 %, respectively) and placebo (35.3 % and 6 %). CONCLUSIONS: Three doses (Months 0,1,6) of toxoid-based C difficile vaccine induced robust neutralizing antibody responses and were well tolerated in healthy participants 65 to 85 years of age. Lot-to-lot consistency was excellent, indicating the manufacturing process for this C difficile vaccine formulation was well controlled. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03579459.

Safety and Immunogenicity of a 20-valent Pneumococcal Conjugate Vaccine in Healthy Infants in the United States.

BACKGROUND: The development and widespread use of pneumococcal conjugate vaccines (PCVs) substantially reduced the global burden of pneumococcal disease. Expanding the serotypes covered by PCVs may further reduce disease burden. A 20-valent PCV (PCV20) has been developed to add coverage for 7 additional serotypes (8, 10A, 11A, 12F, 15B, 22F and 33F) to those in the existing 13-valent PCV (PCV13). This phase 2 study evaluated the safety, tolerability and immunogenicity of PCV20 in healthy US infants. METHODS: In this randomized, active-controlled, double-blind study, 460 infants were randomized 1:1 to receive a 4-dose series of either PCV20 or PCV13 at 2, 4, 6 and 12 months of age. Solicited local reactions and systemic events, adverse events (AEs) and serious AEs were recorded. Immunogenicity was assessed by measuring serotype-specific IgG concentrations and opsonophagocytic activity titers at 1 month after Dose 3, before Dose 4 and 1 month after Dose 4. RESULTS: Of 460 infants, 82.8% completed the 1-month visit after Dose 4. Local reactions and systemic events were mostly mild to moderate in severity and similar between the PCV20 and PCV13 groups. Treatment-related AEs were uncommon, with no related serious AEs or deaths reported. IgG and opsonophagocytic activity responses elicited by PCV20 were robust and demonstrated a booster response after Dose 4. CONCLUSIONS: Administration of PCV20 in US infants was well tolerated, with a safety profile similar to PCV13, and induced robust serotype-specific immune responses. These findings support continued development of PCV20 in the pediatric population.

Phase 1 trial of a 20-valent pneumococcal conjugate vaccine in healthy adults.

INTRODUCTION: Streptococcus pneumoniae is a leading cause of bacteremia, bacterial pneumonia, and meningitis, and is associated with substantial morbidity and mortality, particularly in those under 2 years of age and those over 65 years of age. While significant progress against S. pneumoniae-related disease has been made as a result of the introduction of pneumococcal conjugate vaccines (PCV7, PCV10 and PCV13), there remains value in further expanding pneumococcal vaccine serotype coverage. Here we present the first report of a 20-valent pneumococcal conjugate vaccine (PCV20) containing capsular polysaccharide conjugates present in PCV13 as well as 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) which are important contributors to pneumococcal disease. METHODS: This Phase I first-in-human study was a randomized, controlled, observer-blinded study with a two-arm parallel design to assess the safety, tolerability, and immunogenicity of PCV20 in adults. A total of 66 healthy adults 18-49 years of age with no history of pneumococcal vaccination were enrolled and randomized to receive a single dose of PCV20 or a licensed tetanus, diphtheria, acellular pertussis combination vaccine (Tdap) control. Local injection site reactions, select systemic symptoms, laboratory studies, and adverse events were assessed. Opsonophagocytic activity (OPA) titers and IgG concentrations were measured in sera collected prior to, and approximately one month (28-35 days) after vaccination. RESULTS: Vaccination with PCV20 elicited substantial IgG and functional bactericidal immune responses as demonstrated by increases in IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) to the 20 vaccine serotypes. The overall safety profile of PCV20 was similar to Tdap, and generally consistent with that observed after PCV13 administration. CONCLUSIONS: Vaccination with PCV20 was well tolerated and induced substantial functional (OPA) and IgG responses to all vaccine serotypes. There were no safety issues identified in this Phase 1 study, and the data supported further evaluation of PCV20.