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Staphylococcus aureus is a leading cause of healthcare-associated infections. No preventive vaccine is currently licensed. SA4Ag is an investigational 4-antigen S. aureus vaccine, composed of capsular polysaccharide conjugates of serotypes 5 and 8 (CP5 and CP8), recombinant surface protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (rMntC). This Phase 1 study aimed to confirm the safety and immunogenicity of SA4Ag produced by the final manufacturing process before efficacy study initiation in a surgical population.Healthy adults (18-65years) received one intramuscular SA4Ag injection. Serum functional antibodies were measured at baseline and Day 29 post-vaccination. An opsonophagocytic activity (OPA) assay measured the ability of vaccine-induced antibodies to CP5 and CP8 to kill S. aureus clinical isolates. For MntC and ClfA, antigen-specific immunogenicity was assessed via competitive Luminex® immunoassay (cLIA) and via fibrinogen-binding inhibition (FBI) assay for ClfA only. Reactogenicity and adverse event data were collected.One hundred participants were vaccinated. SA4Ag was well tolerated, with a satisfactory safety profile. On Day 29, OPA geometric mean titers (GMTs) were 45,738 (CP5, 95% CI: 38,078-54,940) and 42,652 (CP8, 95% CI: 32,792-55,477), consistent with 69.2- and 28.9-fold rises in bacteria-killing antibodies, respectively; cLIA GMTs were 2064.4 (MntC, 95% CI: 1518.2-2807.0) and 3081.4 (ClfA, 95% CI: 2422.2-3920.0), consistent with 19.6- and 12.3-fold rises, respectively. Similar to cLIA results, ClfA FBI titers rose 11.0-fold (GMT: 672.2, 95% CI: 499.8-904.2). The vast majority of participants achieved the pre-defined biologically relevant thresholds: CP5: 100%; CP8: 97.9%, ClfA: 87.8%; and MntC 96.9%.SA4Ag was safe, well tolerated, and rapidly induced high levels of bacteria-killing antibodies in healthy adults. A Phase 2B efficacy trial in adults (18-85years) undergoing elective spinal fusion is ongoing to assess SA4Ag's ability to prevent postoperative invasive surgical site and bloodstream infections caused by S. aureus. Clinicaltrials.gov Identifier: NCT02364596.

Background A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. Methods In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18–64 years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). Results A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11–15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. Conclusions Single-dose vaccination of SA4Ag in healthy adults aged 18–64 years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. Trial registration number: NCT01364571

Background The decline in immune function with age is a challenge to vaccine development. Following an initial study in adults aged 18–64 years, this study evaluated the safety and immunogenicity of Staphylococcus aureus (S. aureus) 4-antigen (SA4Ag) and 3-antigen (SA3Ag) vaccine in older adults. SA3Ag included capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to the nontoxic mutant form of diphtheria toxin (CRM197) and a recombinant version of clumping factor A (ClfA). SA4Ag included these antigens, with the addition of a recombinant manganese transporter C (rP305A or MntC). Both vaccines were unadjuvanted. Methods In this double-blind, sponsor-unblinded, placebo-controlled, phase 1/2 study, 284 healthy adults (aged 65–85 years) were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A, SA3Ag, or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; immunogenicity was also assessed using a competitive Luminex® immunoassay (cLIA). T-cell responses were measured in a small subgroup of subjects using intracellular cytokine staining (ICS) assays. Results The results demonstrated rapid and robust functional immune responses to all antigens in healthy older adults. A high proportion of active vaccine recipients met the pre-defined antibody thresholds for each antigen at Day 29. SA4Ag elicited a dose-level response to rP305A with up to a 13-fold rise in cLIA titres at Day 29. Opsonophagocytic activity (OPA) assays showed >50- and >20-fold rises in functional titres using S. aureus strains expressing CP5 and CP8, respectively, at Day 29. T-cell cytokine responses were not substantially above background levels. There were no safety concerns in this study population and no increases in adverse events with higher rP305A dose levels. Conclusions Single-dose vaccination of SA4Ag and SA3Ag in healthy adults aged 65–85 years safely induced rapid and robust functional immune responses, supporting further development of SA4Ag for the prevention of S. aureus disease in adults up to age 85 years. Trial registration number: NCT01643941 .

Background: Neisseria meningitidis serogroup B (MnB) is an important cause of invasive meningococcal disease (IMD). A MnB vaccine (bivalent rLP2086, Trumenba®) consisting of 2 factor H binding protein variants received accelerated approval in the United States for the prevention of IMD caused by MnB in individuals 10-25 years of age. This randomized, active-controlled, observer-blind study further assessed the safety and tolerability of bivalent rLP2086. Methods: Eligible subjects ≥10 to ®) at months 0 and 6, and saline at month 2. The primary endpoints were serious adverse events (SAEs) throughout the study and medically-attended adverse events (MAEs) within 30 days after vaccination. Additional safety assessments included SAEs at other study intervals and adverse events (AEs) during the vaccination phase. Results: Of 5712 subjects randomized, 84.6% (n = 3219) of bivalent rLP2086 recipients and 87.2% (n = 1663) of HAV/saline recipients completed the study. Throughout the study, SAEs were reported for 1.6% and 2.5% of bivalent rLP2086 and HAV/saline recipients, respectively. SAEs related to either vaccine were rare. MAEs occurred in 7.0% and 6.1% of subjects after vaccination 1; 5.5% and 6.1% after vaccination 2; and 5.3% and 5.5% after vaccination 3 in the bivalent rLP2086 and HAV/saline groups, respectively. A greater proportion of subjects reported AEs during the vaccination phase after bivalent rLP2086 compared with HAV/saline recipients; however, when reactogenicity events were excluded, the proportion between groups was similar. Conclusion: This safety study, the largest randomized, active-controlled trial evaluating a recombinant MnB vaccine, demonstrated that bivalent rLP2086 is safe and tolerable in healthy individuals ≥10 to

Background The bivalent rLP2086 vaccine is approved in the United States to prevent meningococcal disease caused by Neisseria meningitidis serogroup B (MnB) in individuals aged 10–25 years. The immunogenicity and safety of bivalent rLP2086 were evaluated in microbiologists 24–62 years old who handle MnB. Methods Seven subjects vaccinated at 0, 2, and 6 months had functional antibodies measured before vaccination and 1 month after each dose by serum bactericidal assays using human complement (hSBAs) and 4 vaccine-heterologous MnB test strains. Results Six subjects qualified for analysis. All demonstrated hSBA titers ≥the lower limit of quantitation (LLOQ) against 3 of 4 strains; 3 subjects achieved titers ≥LLOQ for the fourth. Safety-related events following vaccination were generally mild to moderate in severity. Conclusions Three doses of bivalent rLP2086 were generally well tolerated in laboratory personnel and elicited protective functional immune responses reflective of broad coverage against MnB disease.

Background: The period of heightened risk of invasive meningococcal disease in adolescence extends for >10 years. This study aimed to evaluate persistence of the immune response to the serogroup B meningococcal (MenB) vaccine MenB-FHbp (Trumenba ® , Bivalent rLP2086) under two- and three-dose primary vaccination schedules, both of which are approved in the United States and the European Union, and to assess safety and immunogenicity of a booster dose. Methods: This was an open-label extension study of a phase 2 randomized MenB-FHbp study (primary study). This interim analysis includes data through 1 month after booster vaccination. In the primary study, adolescents 11–18 years of age were randomized using an interactive voice or web-based response system to receive 120 μg MenB-FHbp under 0-, 1-, 6-month; 0-, 2-, 6-month; 0-, 6-month; 0-, 2-month; or 0-, 4-month schedules (termed study groups for the current analysis). For the primary study, participants were blinded to their vaccine study group allocation, but investigators and the study sponsor were unblinded. Immune responses in subjects from the primary study were evaluated through 48 months after primary vaccination (persistence stage; 17 sites in Czech Republic, Denmark, Germany, and Sweden). Safety and immunogenicity of a booster dose given at 48 months after primary vaccination (booster stage; 14 sites in Czech Republic, Denmark, and Sweden) were also assessed. Immune responses were evaluated in serum bactericidal assays with human complement (hSBAs) using four MenB test strains representative of disease-causing MenB strains in the United States and Europe and expressing factor H binding proteins (FHbps) heterologous to the vaccine antigens. The primary immunogenicity endpoints were the proportions of subjects with hSBA titers greater than or equal to the assays’ lower limit of quantitation (LLOQ; 1:8 or 1:16 depending on strain) at 12, 18, 24, 36, and 48 months after primary vaccination (persistence stage) and 1 and 48 months after the primary vaccination series and 1 month after receipt of the booster dose (booster stage). Safety evaluations during the booster stage included local reactions and systemic events by severity, antipyretic use, adverse events (AEs), immediate AEs, serious AEs (SAEs), medically attended AEs (MAEs), newly diagnosed chronic medical conditions (NDCMCs), and missed days of school and work because of AEs. The modified intent-to-treat (mITT) population was used for immunogenicity evaluations in the persistence stage. The booster stage immunogenicity evaluations used the evaluable immunogenicity population; analyses were also performed in the mITT population. For the persistence stage, safety evaluations included subjects with at least one blood draw, whereas for the booster stage, they included subjects who received the booster dose and had available safety data. This trial is registered at ClinicalTrials.gov number NCT01543087. Findings: A total of 465 subjects were enrolled in the persistence stage, and 271 subjects were enrolled in the booster stage. Sera for the extension phase of this interim analysis were collected from September 7, 2012 to December 7, 2015. One month after primary vaccination, 73.8–100.0% of subjects depending on study group responded with hSBA titers ≥LLOQ. Response rates declined during the 12 months after last primary vaccination and then remained stable through 48 months, with 18.0–61.3% of subjects depending on study group having hSBA titers ≥LLOQ at this time point. One month after receipt of the booster dose, 91.9–100.0% of subjects depending on study group had hSBA titers ≥LLOQ against the four primary strains individually and 91.8–98.2% had hSBA titers ≥LLOQ against all four strains combined (composite response). Geometric mean titers were higher after booster vaccination than at 1 month after primary vaccination. Immune responses were generally similar across study groups, regardless of whether a two- or three-dose primary series was received. None of the AEs (2.2–6.9% of subjects depending on study group) or NDCMCs (1.8–5.0%) that were reported during the persistence stage were considered related to the investigational product. Local reactions and systemic events were reported by 84.4–93.8% and 68.8–76.6% of subjects depending on study group, respectively, in the booster stage; these were generally similar across study groups, transient, and less frequent than after any primary vaccination. Additionally, there was no general progressive worsening in severity of reactogenicity events (ie, potentiation; ≤3 subjects per group), and reactogenicity events did not lead to any study withdrawals. No NDCMCs or immediate AEs were reported during the booster stage. AEs were reported by 3.7–12.5% of subjects depending on study group during the booster stage. The two possibly related AEs included a mild worsening of psoriasis and a severe influenza-like illness that resolved in 10 days. Interpretation: Immune responses declined after the primary vaccination series; however, a substantially greater number of subjects retained protective responses at 48 months after primary vaccination compared with subjects having protective responses before vaccination. Persistence trends were similar across all 5 study groups regardless of whether a two- or three-dose primary schedule was received. Furthermore, a booster dose given 48 months after primary vaccination was safe, well-tolerated, and elicited robust immune responses indicative of immunologic memory; these responses were similar between two- and three-dose primary schedule study groups. Use of a booster dose may help further extend protection against MenB disease in adolescents. Funding: Pfizer Inc.

Introduction Clostridium difficile is a significant cause of morbidity and mortality in hospitals, nursing homes, and long-term care facilities. The bacteria can produce 3 toxins, of which the C. difficile toxin A and C. difficile toxin B are the principal virulence factors for C. difficile-associated disease. Methods A phase 1, first-in-human, placebo-controlled, dose-escalation study was performed to assess the safety and immunogenicity of an investigational vaccine candidate consisting of genetically and chemically detoxified, purified toxins A and B. The toxoids, either alone or in combination with aluminum hydroxide (Al(OH)3), were administered to healthy adults 50–85 years of age at antigen dose levels of 50, 100, or 200 μg in a 3-dose regimen administered at 0, 1, and 6 months. Results Overall, the C. difficile vaccine formulations and doses administered were generally well tolerated. Local reactions and systemic events were predominantly mild to moderate, were more common in the 50–64-year age cohort, and comprised mostly injection site pain, headache, and fatigue. In subjects who received the vaccine formulations, both the toxin A- and toxin B-specific neutralizing antibody geometric mean concentrations increased substantially at 1 month after Dose 2 and after Dose 3 compared to baseline. In the 50–64-year age cohort, geometric mean fold rises (GMFRs) in toxin A-specific neutralizing antibodies from baseline at Month 7 ranged from 59.19 to 149.23 in the vaccine groups compared to 2.47 in the control group. For toxin-B specific neutralizing antibodies, the GMFRs from baseline at Month 7 ranged from 116.67 to 2503.75 in the vaccine groups compared to 2.48 in the control group. In the 65–85-year age cohort, GMFRs in toxin A-specific neutralizing antibodies from baseline at Month 7 ranged from 42.73 to 254.77 in the vaccine groups compared to 2.03 in the control group. For toxin-B specific neutralizing antibodies, the GMFRs from baseline at Month 7 ranged from 136.12 to 4922.80 in the vaccine groups compared to 1.58 in the control group. Potent antitoxin neutralizing responses were still evident in immunized subjects in both age groups at Month 12. Although there was no clear dose-level response pattern, the data suggest that both the antitoxin A- and B-specific neutralizing responses were trending higher in the toxoid-only groups compared to the toxoid + Al(OH)3 groups. Furthermore, the magnitude of the immune response was similar in the 2 age cohorts. Conclusion The vaccine formulations studied in this phase 1 study were immunogenic and well tolerated. The results presented support further development of the C. difficile vaccine candidate in a larger population of subjects to determine the optimal dose and immunization schedule. Clinical trial registry NCT01706367 .

Background Many individuals do not respond to a three-dose series of hepatitis B vaccine (HBV) and most do not achieve a protective antibody response until after dose 2 or 3. Methods Healthy, seronegative 18–28 year old adults were randomly assigned in equal numbers to receive two doses of the experimental vaccine (HBV-ISS without alum) (0, 8 weeks) and placebo (24 weeks) or Engerix-B® (0, 8, 24 weeks). Adverse events were collected during the first week and at 4 weeks after each injection. Antibodies were measured 4 weeks after dose 1; before, 1 and 4 weeks after dose 2, and before, 1 and 4 weeks after dose 3 and at 1 year. Results Ninety-nine participants were enrolled (65% female; mean age 22.6 years). 79% of HBV-ISS and 12% of Engerix-B® recipients had a protective antibody response 4 weeks post dose 1 (geometric mean concentration [GMC] 23.0 and 1.87 mIU/mL, respectively). By 1 week post dose 2, 100% of HBV-ISS and 18% Engerix-B® recipients had protective levels (GMC 1603 versus 2.40 mIU/mL). Rates of adverse events were low and similar in both groups; headache and fatigue were the most common systemic adverse events in up to 1/3 of both groups. Mild injection-site tenderness was more common after HBV-ISS than Engerix-B® after both doses (74–77% compared to 34–58%; p ≤ 0.029). Conclusions Protective levels are achieved more quickly and after fewer doses of HBV-ISS than Engerix-B®. HBV-ISS is well tolerated but associated with more mild injection-site tenderness than Engerix-B®.

Certain oligodeoxynuclotides with CpG motifs provide enhanced immune response to co-delivered antigens. We performed a phase I, observer-blinded, randomized study in healthy anti-hepatitis B surface antigen (anti-HBsAg) antibody negative adults to explore safety and immunogenicity of co-injection of recombinant HBsAg combined with an immunostimulatory DNA sequence (ISS) 1018 ISS. Four ISS dosage groups (N=12 per group) were used: 300, 650, 1000 or 3000 microg. For each group, two controls received 20 microg HBsAg alone, two controls received ISS alone, and eight subjects received ISS+20 microg HBsAg. Subjects received two doses 8 weeks apart. Injection site reactions (tenderness and pain on limb movement) were more frequent at higher ISS+HBsAg doses but were mainly mild and of short duration. Higher anti-HBsAg antibody levels were associated with higher ISS doses. Four weeks after the first dose, a seroprotective titer (>or=10 mIU/ml) was noted for 0, 25, 75, and 87.5% of subjects by increasing ISS dose group (P

The safety and immunogenicity of a novel hepatitis B virus (HBV) vaccine containing recombinant PreS2 and S antigens combined with MF59 adjuvant (HBV/MF59) was evaluated in healthy adults (N=230) who were randomized to receive 2 or 3 immunizations of either the study vaccine or a licensed control vaccine (Recombivax HB®). After a single immunization, 105 of 118 (89%) recipients of HBV/MF59 achieved protective serum levels of anti-HBs antibody (>10 mIU/ml), compared with 13 of 110 (12%) recipients of licensed vaccine (P

BackgroundStaphylococcus aureus is a common cause of healthcare-acquired morbidity and mortality and increased healthcare resource utilization. A prophylactic vaccine is being developed that may reduce this disease burden.MethodsVolunteers in good general health aged 50–85 (n=312) and 18–24 (n=96) years were randomized to receive a single intramuscular dose of one of three dose levels of a non-adjuvanted, 3-antigen S. aureus vaccine (SA3Ag) or placebo. SA3Ag antigens included capsular polysaccharides 5 and 8 (CP5 and CP8), each conjugated to cross-reactive material 197 (CRM197), and recombinant clumping factor A (ClfA). Safety, tolerability, and immunogenicity were evaluated.ResultsAt day 29 post-vaccination, robust immune responses were observed in both age cohorts at all three SA3Ag dose levels. In the primary analysis population, the 50- to 85-year age stratum, geometric mean-fold-rises in competitive Luminex® immunoassay antibody titers from baseline ranged from 29.2 to 83.7 (CP5), 14.1 to 31.0 (CP8), and 37.1 to 42.9 (ClfA), all (P