HPLC-MS/MS-based quantification of human monoclonal antibodies targeting SARS-CoV-2 in the presence of endogenous SARS-CoV-2 antibodies in human serum.

Antibodies for treatment and prophylaxis against SARS-CoV-2 are needed particularly for immunocompromised individuals, who cannot adequately benefit from vaccination. To address this need, Aerium Therapeutics is developing antibodies targeting the SARS-CoV-2 spike protein. A bioanalytical method to quantify fully human monoclonal antibodies in a population with widely varying anti-spike antibody titers is required to investigate the pharmacokinetics of these antibodies in clinical trials. To eliminate interference from endogenous anti-spike protein antibodies, an HPLC-MS/MS assay was developed to quantify the investigational monoclonal antibodies (AER001 and AER002) by targeting signature peptides spanning the monoclonal antibodies' CDR regions. By optimizing and comparing affinity capture and ammonium sulphate precipitation, it was demonstrated that both procedures allowed accurate and precise quantification of AER001 and AER002 in human serum with comparable sensitivity. Ammonium sulphate precipitation outperformed immunocapture due to its simplicity and speed at lower cost and a full bioanalytical method validation was performed in human serum. The assay was also validated for human nasal lining fluid extract with a 50-fold lower limit of quantification and was shown to deliver similar sensitivity to previously published affinity capture HPLC-MS/MS assays. Finally, the CDR-derived signature peptides were also generated by tryptic digestion of blank serum in some individuals, an important caveat for HPLC-MS/MS strategies targeting human monoclonal antibodies. In summary, the presented results show that ammonium sulphate precipitation and HPLC-MS/MS allow accurate and precise quantification of monoclonals in clinical studies. The developed methods demonstrate that HPLC-MS/MS can reliably quantify human monoclonal antibodies even when endogenous antibodies with overlapping specificities are present and are crucial for the clinical testing of two investigational COVID-19 monoclonals.

A First-in-Human Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics, and Neutralization Profile of Two Investigational Long-Acting Anti-SARS-CoV-2 Monoclonal Antibodies.

INTRODUCTION: COVID-19 remains a significant risk for the immunocompromised given their lower responsiveness to vaccination or infection. Therefore, passive immunity through long-acting monoclonal antibodies (mAbs) offers a needed approach for pre-exposure prophylaxis (PrEP). Our study evaluated safety, anti-SARS-CoV-2 neutralizing activity, nasal penetration, and pharmacokinetics (PK) of two half-life-extended investigational mAbs, AER001 and AER002, providing the first demonstration of upper airway penetration of mAbs with the LS-modification. METHODS: This randomized, double-blind, placebo-controlled phase I study enrolled healthy adults (n = 80) who received two long-acting COVID mAbs (AER001 and AER002), AER002 alone, or placebo. The dose ranged from 100 mg (mg) to 1200 mg per mAb component. The primary objective was to describe the safety and tolerability following intravenous (IV) administration. Secondary objectives were to describe PK, anti-drug antibodies (ADA), neutralization activity levels, and safety evaluation through 6 months of follow-up. RESULTS: The majority (97.6%) of the reported adverse events (AE) post administration were of grade 1 severity. There were no serious adverse events (SAE) or ADAs. AER001 and AER002 successfully achieved an extended half-life of 105 days and 97.5 days, respectively. Participants receiving AER001 and AER002 (300 mg each) or AER002 (300 mg) alone showed 15- and 26-fold higher neutralization levels against D614G and omicron BA.1 than the placebo group 24 h post-administration. Single 300 or 1200 mg IV dose of AER001 and AER002 resulted in nasal mucosa transudation of approximately 2.5% and 2.7%, respectively. CONCLUSION: AER001 and AER002 showed an acceptable safety profile and extended half-life. High serum neutralization activity was observed against D614G and Omicron BA.1 compared to the placebo group. These data support that LS-modified mAbs can achieve durability, safety, potency, and upper airway tissue penetration and will guide the development of the next generation of mAbs for COVID-19 prevention and treatment. TRIAL REGISTRATION: EudraCT Number 2022-001709-35 (COV-2022-001).

Cervical High-Grade Squamous Intraepithelial Lesion Burden and Standard of Care Treatment Effectiveness and Safety in the United States, 2008-2018: The EACH-WOMAN Project.

OBJECTIVE: Management of cervical high-grade squamous intraepithelial lesions (HSILs), the immediate precursor of cervical cancer, consists largely of surgical treatment for women at higher risk for progression to cancer. The authors' objective was to describe the occurrence of cervical HSIL in the United States and various outcomes for women who received surgical treatment. METHODS: From a US commercial health insurer, a cohort of adult women with cervical HSIL diagnoses receiving surgical treatment within 3 months of diagnosis between January 2008 and September 2018 was identified. This cohort was followed for several outcomes, including cervical HSIL recurrence, human papillomavirus clearance, preterm birth, infection, and bleeding. RESULTS: The incidence rate of cervical HSIL declined from 2.34 (95% CI = 2.30-2.39) cases per 1,000 person-years in 2008 to 1.39 (95% CI = 1.35-1.43) cases per 1,000 person-years in 2014, remaining near that level through 2018. Among 65,527 women with cervical HSIL, 47,067 (72%) received surgical treatment within 3 months of diagnosis. Among the women receiving surgical treatment, cervical HSIL recurred in 6% of surgically treated women, whereas 45% of surgically treated women underwent subsequent virological testing that indicated human papillomavirus clearance. Preterm birth was observed in 5.9% by 5 years follow-up and bleeding and infection each at 2.2% by 7 days follow-up. CONCLUSIONS: From 2008 through 2018, the incidence of diagnosed cervical HSIL decreased for several years before stabilizing. Surgical treatment of HSIL may be beneficial in removing the precancerous lesion, but cervical HSIL may recur, and the surgery is associated with complications including preterm birth, infection, and bleeding.

Durability of protection and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine over 6 months.

BackgroundWe report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.MethodsAdults at increased risk of SARS-CoV-2 infection were randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCR-positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.FindingsData cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.ConclusionAZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registrationClinicalTrials.gov NCT04516746.FundingAstraZeneca; US government.

Thrombosis with thrombocytopenia after AZD1222 (ChAdOx1 nCov-19) vaccination: Case characteristics and associations.

BACKGROUND: Post-marketing surveillance for COVID-19 vaccines during the pandemic identified an extremely rare thrombosis with thrombocytopenia syndrome (TTS) reported post-vaccination, requiring further characterisation to improve diagnosis and management. METHODS: We searched the AstraZeneca Global Safety Database (through April 26, 2021) for cases with co-reported thrombocytopenia and thrombosis (using standardised MedDRA queries/high-level terms) following AZD1222 (ChAdOx1 nCoV-19). Cases were adjudicated by experts as 'typical','possible', 'no' or 'unknown' according to available TTS criteria. Additional confirmatory datasets (May 20-June 20, October 1-December 28) were evaluated. FINDINGS: We identified 573 reports, including 273 (47.6 %) 'typical' and 171 (29.8 %) 'possible' TTS cases. Of these 444 cases, 275 (61.9 %) were female, median age was 50.0 years (IQR: 38.0-60.0). Cerebral venous sinus thrombosis was reported in 196 (44.1 %) cases, splanchnic venous thrombosis in 65 (14.6 %) and thromboses at multiple sites in 119 (26.8 %). Median time to onset was 12.0 days (IQR: 9.0-15.0). Comparison with a pre-pandemic reference population indicated higher rates of autoimmune disorders (13.8 %, 4.4 %), previous heparin therapy (7.4 %, 1.2 %), history of thrombosis (5.5 %, 1.4 %), and immune thrombocytopenia (6.1 %, 0.2 %). Fatality rate was 22.2 % (127/573) overall and 23.6 % (105/444) in 'typical'/'possible' TTS, which decreased from 39.0 % (60/154) in February/March to 15.5 % (45/290) in April. Overall patterns were similar in confirmatory datasets. CONCLUSIONS: The reporting rate of 'typical'/'possible' TTS post first-dose vaccination in this dataset is 7.5 per million vaccinated persons; few cases were reported after subsequent doses, including booster doses. Peak reporting coincided with media-driven attention. Medical history differences versus a reference population indicate potentially unidentified risk factors. The decreasing fatality rate correlates with increasing awareness and publication of diagnostic/treatment guidelines. Adjudication was hindered by unreported parameters, and an algorithm was developed to classify potential TTS cases; comprehensive reporting could help further improve definition and management of this extremely rare syndrome.

Serum levels of anti-PF4 IgG after AZD1222 (ChAdOx1 nCoV-19) vaccination.

Rare cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported after AZD1222. Anti-platelet factor-4 (PF4) antibodies were observed in patients following presentation of TTS, however it is unclear if AZD1222 was responsible for inducing production of anti-PF4. Paired samples (baseline and day-15) from a phase 3 trial of AZD1222 vs placebo were analyzed for anti-PF4 levels; 19/1727 (1.1%, AZD1222) vs 7/857 (0.8%, placebo) participants were anti-PF4-IgG-negative at baseline but had moderate Day-15 levels (P = 0.676) and 0/35 and 1/20 (5.0%) had moderate levels at baseline but high Day-15 levels. These data indicate that AZD1222 does not induce a clinically relevant general increase in anti-PF4 IgG.

Durability of response to VGX-3100 treatment of HPV16/18 positive cervical HSIL.

VGX-3100 is an investigational DNA-based immunotherapy being developed as an alternative to surgery and ablation for cervical High-Grade Squamous Intraepithelial Lesion (HSIL) with the aim of preserving reproductive health while treating precancerous disease. Response durability up to 1.5 y following dosing is now reported.Histologic regression and HPV16 and/or HPV 18 (HPV16/18) clearance were previously demonstrated in a randomized, placebo-controlled, double-blind trial and reported for 6 months after the last dose of VGX-3100 or placebo. The presence of HPV16/18, Pap smear diagnoses, and immunogenicity longer-term responses were assessed at 18 months after the last dose.91% (32/35) VGX-3100-treated women, whose cervical HSIL regressed and avoided excision at 6 months following study treatment completion, had no detectable HPV16/18 at 18 months following treatment completion. These results were comparable to those for women who received placebo and then later underwent surgery. For VGX-3100 recipients who regressed at 6 months following study treatment completion and avoided excision during the trial, Pap testing showed no HSIL recurrence at 18 months following VGX-3100 treatment. VGX-3100-induced cellular immune responses specific for HPV 16/18 E6/E7 remained higher than for placebo control recipients at 18 months.In women with cervical HSIL who responded to VGX-3100 and were able to avoid surgery, clinical outcomes were comparable to the placebo control group which underwent conventional surgical treatment. These findings extend the understanding of the durability of the treatment effect of VGX-3100 up to 1.5 y and support that VGX-3100 could be used as an alternative to surgery.

Safety and immunogenicity of VGX-3100 formulations in a healthy young adult population.

HPV remains the most common sexually transmitted disease worldwide, despite improvements in awareness, screening, prophylactic vaccination uptake, and surgical treatment. VGX-3100 is an immunotherapy that uses electroporation to introduce DNA encoding for modified HPV-16 and HPV-18, E6-and E7 proteins into myocytes to stimulate an effector T cell response. We now report immunogenicity and safety of VGX-3100 for a refrigeration-stable formulation, which improves patient-care setting usability. This multi-arm, double-blinded, randomized trial enrolled 235 healthy men and women to receive either a refrigerated (RF) or frozen formulation (FF) of VGX-3100. Three doses were administered intramuscularly with electroporation at 0, 4, and 12 weeks. Non-inferiority of RF to FF was assessed by comparing the proportion of subjects who achieved a ≥2-fold increase from baseline to Week 14 in Spot Forming Units/106 PMBCs using an interferon-γ enzyme-linked immunospot assay. There were no related SAEs. Injection site reactions were the most common adverse event (54%, RF; 66%, FF) the majority of which resolved within a few minutes following administration. The primary endpoint was met with 89.9% of RF recipients and 97.2% of FF recipients reaching a ≥2-fold rise in SFU/106 PBMC, 2 weeks following the last dose; RF was statistically non-inferior to FF (p = .022). A systemic, immunologic approach has the potential to fill a critical gap in the ability to treat men and women with high grade HPV diseases. These safety and immunogenicity data are supportive of the continued development of a refrigerated formulation of VGX-3100.

A Phase 2, Randomized, Active-controlled, Observer-blinded Study to Assess the Immunogenicity, Tolerability and Safety of Bivalent rLP2086, a Meningococcal Serogroup B Vaccine, Coadministered With Tetanus, Diphtheria and Acellular Pertussis Vaccine and Serogroup A, C, Y and W-135 Meningococcal Conjugate Vaccine in Healthy US Adolescents.

BACKGROUND: Bivalent rLP2086, targeting meningococcal serogroup B, will extend prevention of meningococcal disease beyond that provided by quadrivalent serogroup ACWY vaccines; coadministration with recommended vaccines may improve adherence to vaccine schedules. This phase 2, randomized, active-controlled, observer-blinded study assessed whether immune responses induced by coadministration of Menactra (meningococcal A, C, Y and W-135 polysaccharide conjugate vaccine [MCV4]) and Adacel (tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine [Tdap]) with bivalent rLP2086 (Trumenba [meningococcal serogroup B vaccine], approved in the United States) were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. METHODS: Healthy adolescents aged 10 to <13 years received MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap or bivalent rLP2086. Bivalent rLP2086 response was assessed with serum bactericidal assays using human complement with 2 meningococcal serogroup B test strains expressing vaccine-heterologous factor H-binding protein variants; MCV4 with SBAs using rabbit complement; and Tdap with multiplexed Luminex assays. Safety was evaluated. RESULTS: Two thousand six hundred forty-eight subjects were randomized. Immune responses to MCV4 + Tdap + bivalent rLP2086 were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. Seroprotective serum bactericidal assays using human complement titers were documented for 62.3%-68.0% and 87.5%-90% of MCV4 + Tdap + bivalent rLP2086 recipients after doses 2 and 3, respectively. A ≥4-fold rise in serum bactericidal assays using human complement titers from baseline was achieved by 56.3%-64.3% and 84.0%-85.7% of subjects after doses 2 and 3, respectively. Bivalent rLP2086 alone induced similar responses. Concomitant administration did not substantially increase reactogenicity compared with bivalent rLP2086 alone. CONCLUSIONS: Bivalent rLP2086 given concomitantly with MCV4 + Tdap met all noninferiority immunogenicity criteria without a clinically meaningful increase in reactogenicity. MCV4 and bivalent rLP2086 coadministration would provide coverage against the 5 major disease-causing serogroups.

Immunogenicity, Tolerability and Safety in Adolescents of Bivalent rLP2086, a Meningococcal Serogroup B Vaccine, Coadministered with Quadrivalent Human Papilloma Virus Vaccine.

BACKGROUND: This study in healthy adolescents (11 to <18 years) evaluated coadministration of quadrivalent human papillomavirus vaccine (HPV-4), with bivalent rLP2086, a meningococcal serogroup B (MnB) vaccine. METHODS: Subjects received bivalent rLP2086 + HPV-4, bivalent rLP2086 + saline or saline + HPV-4 at 0, 2 and 6 months. Immune responses to HPV-4 antigens were assessed 1 month after doses 2 and 3. Serum bactericidal assays using human complement (hSBAs) with 4 MnB test strains expressing vaccine-heterologous human complement factor H binding protein (fHBP) variants determined immune responses to bivalent rLP2086. Coprimary objectives were to demonstrate noninferior immune responses with concomitant administration compared with either vaccine alone. Additional endpoints included the proportions of subjects achieving prespecified protective hSBA titers to all 4 MnB test strains (composite response) and ≥4-fold increases in hSBA titer from baseline for each test strain after dose 3; these endpoints served as the basis of licensure of bivalent rLP2086 in the US. RESULTS: The noninferiority criteria were met for all MnB test strains and HPV antigens except HPV-18; ≥99% of subjects seroconverted for all 4 HPV antigens. Bivalent rLP2086 elicited a composite response in >80% of subjects and increased hSBA titers ≥4-fold in ≥77% of subjects for each test strain after dose 3. A substantial bactericidal response was also observed in a large proportion of subjects after dose 2. Local reactions and systemic events did not increase with concomitant administration. CONCLUSIONS: Concomitant administration of bivalent rLP2086 and HPV-4 elicits robust immune responses to both vaccines without increasing reactogenicity compared with bivalent rLP2086 alone. Concurrent administration may increase compliance with both vaccine schedules.

Repurposing historical control clinical trial data to provide safety context.

Billions of dollars spent, millions of subject-hours of clinical trial experience and an abundance of archived study-level data, yet why are historical data underutilized? We propose that historical data can be aggregated to provide safety, background incidence rate and context to improve the evaluation of new medicinal products. Here, we describe the development and application of the eControls database, which is derived from the control arms of studies of licensed products, and discuss the challenges and potential solutions to the proper application of historical data to help interpret product safety.

Immunogenicity, safety, and tolerability of the meningococcal serogroup B bivalent rLP2086 vaccine in adult laboratory workers.

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.

Safety and immunogenicity of a recombinant hepatitis B vaccine manufactured by a modified process in renal pre-dialysis and dialysis patients.

BACKGROUND: Patients with renal insufficiency are hyporesponsive to vaccination, including to hepatitis B vaccines. A manufacturing process modification for a hepatitis B vaccine (mpHBV) was studied in renal pre-dialysis and dialysis patients. METHODS: This randomized, open-label, multicenter, estimation study enrolled previously unvaccinated, HBV-seronegative adult dialysis and pre-dialysis patients (N=276, median age 72.0 years). At 0, 1, 6, and 8 months, group 1 received a 1 mL intramuscular dose of mpHBV (containing 40 µg HBsAg) as a single injection, while group 2 received a 1 mL intramuscular dose of a licensed hepatitis B vaccine as two injections (each containing 20 µg HBsAg; 40 µg HBsAg total). Serum antibody to HBsAg (anti-HBs) was measured predose 1, and 1 month postdose 3 and 4. Anti-HBs geometric mean concentration (GMC) and seroprotection rate (SPR, % of subjects with anti-HBs titer ≥10 mIU/mL) were estimated at months 7 and 9. RESULTS: For group 1, month 7 SPR was 48.5% (49/101, 95% CI: 38.4%, 58.7%); with an additional dose, month 9 SPR increased to 66.7% (66/99, 95% CI: 56.5%, 75.8%). For group 2, month 7 SPR was 57.7% (64/111, 95% CI: 47.9%, 67.0%); with an additional dose, month 9 SPR increased to 69.2% (72/104, 95% CI: 59.4%, 77.9%). group 1 GMCs at months 7 and 9 were 27.5 mIU/mL (95% CI: 15.7, 48.0) and 61.7 mIU/mL (95% CI: 34.2, 111.5), respectively. group 2 GMCs at months 7 and 9 were 48.7 mIU/mL (95% CI: 28.7, 82.7) and 115.8 mIU/mL (95% CI: 65.2, 205.5), respectively. There were 22 serious adverse events; none were considered related to study vaccine. CONCLUSIONS: Both formulations were immunogenic in this population but required more vaccinations to reach seroprotective levels than comparable regimens in healthy individuals, as expected. The relatively reduced SPRs seen in this population support the need for routine screening and re-dosing in this population.

Safety and immunogenicity of a toddler dose following an infant series of a hexavalent diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b, hepatitis B vaccine administered concurrently or at separate visits with a heptavalent pneumococcal conjugate vaccine.

BACKGROUND: Combination diphtheria-tetanus-5 component acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B vaccine (DTaP5-IPV-Hib-HepB) administered either concurrently with 7-valent pneumococcal conjugate vaccine (PCV7) or 1 month apart was generally safe and immunogenic at 2, 4 and 6 months of age. This study examined the effects of a booster dose at age 15 months. METHODS: Participants were randomized to DTaP5-IPV-Hib-HepB plus PCV7, DTaP5-IPV-Hib-HepB with PCV7 administered 1 month later or a pentavalent DTaP5-IPV/Hib plus HepB plus PCV7 at 15 months of age in a randomized, open-label, phase IIb clinical trial. Immunogenicity endpoints were rates of seroresponse to pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae types 2 and 3; rates of seroprotection against (Hib) polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus types 1, 2 and 3; and geometric mean titers to all vaccine antigens. Safety endpoints included solicited injection-site reactions and systemic and serious adverse events. RESULTS: Seroresponse/seroprotection rates for all antigens exceeded prespecified criteria in both groups that received the hexavalent DTaP5-IPV-Hib-HepB; in the group that received the currently licensed pentavalent vaccine, seroresponse/seroprotection rates exceeded the criteria for all antigens except filamentous hemagglutinin. Seroresponse rates were ≥88.9% for pertussis antigens and seroprotection rates against polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus antigens were ≥95.1% in recipients of DTaP5-IPV-Hib-HepB. CONCLUSIONS: DTaP5-IPV-Hib-HepB administered concomitantly with PCV7 or 1 month apart at 15 months of age following the infant series was well-tolerated and elicited antibody responses to all vaccine antigens, with no significant interference from concomitant PCV7 administration (clinicaltrials.gov registration number NCT00362427).

Safety and immunogenicity of a hexavalent vaccine administered at 2, 4 and 6 months of age with or without a heptavalent pneumococcal conjugate vaccine: a randomized, open-label study.

BACKGROUND: DTaP5-IPV-Hib-HepB, an investigational hexavalent combination vaccine, was evaluated for safety and immunogenicity, when administered to infants with heptavalent pneumococcal conjugate vaccine (PCV7). METHODS: Infants were randomized to receive DTaP5-IPV-Hib-HepB plus PCV7, DTaP5-IPV-Hib-HepB with PCV7 administered 1 month later or DTaP5-IPV/Hib plus HepB plus PCV7 at 2, 4 and 6 months of age in an open-label, phase IIb trial. Vaccine responses were assessed by pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae types 2/3 seroconversion rates, Haemophilus influenzae type b polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus types 1, 2 and 3 seroprotection rates and geometric mean titers. Solicited injection site and systemic reactions, serious adverse events, and other safety outcomes were reported. RESULTS: Seroprotection rates to polyribosylribitol phosphate, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus antigens across all groups met or exceeded predetermined acceptability criteria. Seroconversion rates to pertussis toxoid, pertactin and fimbriae types 2/3, but not filamentous hemagglutinin, met such criteria. Antidiphtheria antibodies were significantly lower when PCV7 was coadministered. Geometric mean titers to the other antigens of the hexavalent and PCV7 vaccines were all high and similar in the 2 groups. No safety signals were noted. CONCLUSIONS: DTaP5-IPV-Hib-HepB administered at 2, 4 and 6 months of age concomitantly with PCV7 was well tolerated and elicited robust antibody responses to all but the antidiphtheria antigens for which there may be evidence of immune interference. Only filamentous hemagglutinin did not meet seroconversion rate acceptability criteria.

Safety and immunogenicity of a modified process hepatitis B vaccine in healthy neonates.

BACKGROUND: A manufacturing process using a modified adjuvant was developed to optimize the consistency and immunogenicity for recombinant hepatitis B vaccine (control: RECOMBIVAX-HB™). This modified process hepatitis B vaccine (mpHBV), which was previously shown to have an acceptable safety and immunogenicity profile in young adults, has now been studied in newborn infants. METHODS: Healthy 1-10-day-old neonates (N=566) received 3 intramuscular doses (5µg hepatitis B surface antigen [HBsAg] per dose) of either mpHBV or control at Day 1, and Months 1 and 6. Serum antibody to HBsAg (anti-HBs) was assayed at Month 7 (1 month Postdose 3). Anti-HBs geometric mean titers (GMTs) and seroprotection rates (SPRs) (% of subjects with an anti-HBs titer ≥10mIU/mL) were compared at Month 7. After each dose, injection-site adverse experiences (AEs) and axillary temperatures were recorded for 5 days; systemic AEs were recorded for Days 1-14. RESULTS: Month 7 SPR was 97.9% for the mpHBV group and 98.9% for the control. The GMT was 843.7mIU/mL for the mpHBV group and 670.1mIU/mL for the control. The GMT ratio (mpHBV/control) was 1.26 (95% confidence interval [CI]: 0.94, 1.69), meeting the prespecified non-inferiority criteria. The percentages of subjects reporting any AE, injection-site AEs, or systemic AEs were similar across the 2 vaccination groups. There were no serious AEs. CONCLUSIONS: The safety profile of mpHBV was comparable to that of the control vaccine. The geometric mean antibody titer for mpHBV was higher than control vaccine in this infant population, but the difference did not meet the predefined statistical criterion for superiority.

Safety and immunogenicity of a modified process hepatitis B vaccine in healthy adults ≥50 years.

BACKGROUND: Generating protective immune responses in older adults (particularly ≥65 y) remains challenging for vaccines in general. This study examined the immune response engendered in older adults by RECOMBIVAX HB™ manufactured using a modified adjuvant (modified-process hepatitis B vaccine; mpHBV), RECOMBIVAX-HB™, and ENGERIX-B™. METHODS: Randomized, double-blind, multicenter study enrolled healthy, seronegative subjects (N=538) to receive mpHBV (10 µg hepatitis B surface antigen [HBsAg]), RECOMBIVAX-HB™ (10 µg HBsAg), or ENGERIX-B™ (20 µg HBsAg) at Day 1, Month 1, and Month 6. Prespecified analysis of subpopulations 50-64 y and ≥65 y was conducted. Serum antibody to HBsAg (anti-HBs) was measured Predose 1 and 1 mo Postdose 3. RESULTS: For subjects ≥50 y, seroprotection rates (SPR, anti-HBs titer ≥10 mIU/mL) were 75.7% (95% CI: 68.0,82.2) for mpHBV, 68.0% (95% CI: 59.8,75.5) for RECOMBIVAX HB™, and 84.0% (95% CI: 77.0,89.6) for ENGERIX-B™. For subjects 50-64 y, SPRs were 82.1% (95% CI: 73.8,88.7) for mpHBV, 77.4% (95% CI: 68.7,84.7) for RECOMBIVAX-HB™, and 88.5% (95% CI: 81.1,93.7) for ENGERIX-B™. For subjects ≥65 y, SPRs were 57.5% (95% CI: 40.9,73.0) for mpHBV, 34.4% (95% CI: 18.6,53.2) for RECOMBIVAX-HB™, and 67.7% (95% CI: 48.6,83.3) for ENGERIX-B™. There were 6 non-vaccine related serious adverse events reported. CONCLUSIONS: The majority of subjects ≥50 y old achieved seroprotection. The sub-population ≥65 y had lower vaccination responses than the 50-64 y sub-population. For subjects ≥65 y, mpHBV and ENGERIX-B™ groups achieved higher seroprotection rates than the RECOMBIVAX-HB group. The safety profile of mpHBV was consistent with the other groups.