Antibody Kinetics and Response to Routine Vaccinations in Infants Born to Women Who Received an Investigational Trivalent Group B Streptococcus Polysaccharide CRM197-Conjugate Vaccine During Pregnancy.

BACKGROUND: Maternal vaccination against group B Streptococcus (GBS) might provide protection against invasive GBS disease in infants. We investigated the kinetics of transplacentally transferred GBS serotype-specific capsular antibodies in the infants and their immune response to diphtheria toxoid and pneumococcal vaccination. METHODS: This phase 1b/2, observer-blind, single-center study (NCT01193920) enrolled infants born to women previously randomized (1:1:1:1) to receive either GBS vaccine at dosages of 0.5, 2.5, or 5.0 µg of each of 3 CRM197-glycoconjugates (serotypes Ia, Ib, and III), or placebo. Infants received routine immunization: combination diphtheria vaccine (diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine; age 6/10/ 14 weeks) and 13-valent pneumococcal CRM197-conjugate vaccine (PCV13; age 6/14 weeks and 9 months). Antibody levels were assessed at birth, day (D) 43, and D91 for GBS serotypes; 1 month postdose 3 (D127) for diphtheria; and 1 month postprimary (D127) and postbooster (D301) doses for pneumococcal serotypes. RESULTS: Of 317 infants enrolled, 295 completed the study. In infants of GBS vaccine recipients, GBS serotype-specific antibody geometric mean concentrations were significantly higher than in the placebo group at all timepoints and predictably decreased to 41%-61% and 26%-76% of birth levels by D43 and D91, respectively. Across all groups, ≥95% of infants were seroprotected against diphtheria at D127 and ≥91% of infants had seroprotective antibody levels against each PCV13 pneumococcal serotype at D301. CONCLUSIONS: Maternal vaccination with an investigational CRM197-glycoconjugate GBS vaccine elicited higher GBS serotype-specific antibody levels in infants until 90 days of age, compared with a placebo group, and did not affect infant immune responses to diphtheria toxoid and pneumococcal vaccination. CLINICAL TRIALS REGISTRATION: NCT01193920.

Bridging the Access Gap for Comprehensive Sickle Cell Disease Management Across Sub-Saharan Africa: Learnings for Other Global Health Interventions?

Background: Sickle cell disease (SCD) is a major unresolved global health issue, with the highest disease burden in sub-Saharan African countries; yet, SCD care has not proportionally reached patients in these regions, and the disease has received limited attention in the past. Addressing the burden of SCD in sub-Saharan Africa requires a holistic, collaborative approach to ensure solutions are both comprehensive - i.e., cover the entire continuum of care from early diagnosis to treatment - and sustainable - i.e., are co-created and co-owned with local partners and integrated into existing local systems to enable long-term independence without the need for continuous external support. Objective: We outline a set of recommendations for enhancing the provision of comprehensive healthcare for prevalent diseases in resource-constraint settings, gathered from the Novartis Africa SCD Program, that could serve as 'blueprint' for public-private partnerships to tackle global health priorities. Methods: The Novartis Africa SCD program was initiated with the aim to bridge access gaps to SCD care and provide comprehensive and innovative treatment solutions for SCD, especially in SSA where the disease burden is highest. The Program was first inaugurated in 2019 in Ghana through a public-private partnership with the Ministry of Health of the Government of Ghana, the Ghana Health Service, and the Sickle Cell Foundation of Ghana. Through engagement with these partners, as well as with support from other organizations with complementary competencies and resources, several targeted solutions were implemented to help strengthen the healthcare ecosystem to allow for comprehensive SCD management. Learnings from these interventions are highlighted as best practice consideration as a catalyst and to activate more public-private actors for this neglected global health issue. Findings and Conclusions: A solid understanding of the access barriers to comprehensive care has to be acquired by listening to and learning from patients, civil society, and local experts. Access barriers need to be addressed at multiple levels, i.e., by not only making medicines available and affordable, but also by strengthening healthcare systems, building capacity, and fostering local research and development. Partnerships across governmental, public, academic, non-profit, and private organizations are needed to secure political will, pool resources, gather expertise with understanding of the local context, and allow integration into all levels of existing local healthcare structures and the wider society.

Leading a Digital Transformation in the Pharmaceutical Industry: Reimagining the Way We Work in Global Drug Development.

We are experiencing seminal times in computing that seem to define a fourth industrial revolution. This may fundamentally change the way we live, work, and relate to one another. Embracing data and digital information is a top priority for most industries these days, and Life Sciences is no exception. The pharmaceutical industry in particular is fundamentally a data-driven business. Inspired by a desire to "Go Big on Data," we developed a strategic roadmap defining a digital transformation to reimagine the way we work in Novartis Global Drug Development, leveraging data science to generate and inject actionable insights into our best practices. We launched a program called Nerve Live, and built a state-of-the-art data and analytics platform to harness past and present operational data, providing access to decades of drug development "experience" buried across multiple sources. The platform enabled the systematic application of machine learning and predictive analytics to generate "intelligence": new insights across multiple functional areas. To action the insights and create "value," we crafted skillfully designed end-user applications for domain experts to plan, track, predict, compare and monitor domain activities, optimize costs, and maximize quality. Today, the Nerve Live program enables insights-driven decision making at scale, unlocking productivity, and providing transparency across the Novartis Global Drug Development organization and beyond. We identified three main drivers making the Nerve Live program successful and enabling the associated digital transformation to flourish. We discuss the challenges, highlight the benefits, and see the importance of leading the way to become future proof.

Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial.

BACKGROUND: Maternal group B streptococcus (GBS) serotype-specific capsular antibody concentrations are correlated with susceptibility to neonatal GBS invasive disease. Maternal immunisation against GBS during pregnancy might protect infants across the period of susceptibility to invasive disease, but no licensed vaccine exists. This study assessed the safety and immunogenicity of a CRM197-conjugated trivalent GBS vaccine in non-pregnant and pregnant women, and antibody transfer to their infants. METHODS: We did a phase 1b/2, randomised, observer-blind single-centre study of an investigational trivalent GBS vaccine in healthy non-pregnant women (cohort 1), and a dose-ranging study in healthy pregnant women (cohort 2). The study was done at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Participants were healthy non-pregnant or pregnant (28-35 weeks' gestation) women aged 18-40 years. In cohort 1, non-pregnant women were randomly assigned (2:1) to receive the investigational vaccine (two injections, 1 month apart, of a 20 µg dose [of each serotype] of aluminium hydroxide-adjuvanted investigational vaccine) or placebo. In cohort 2, pregnant women were randomly assigned (1:1:1:1) to receive one injection at 28-35 weeks' gestation of 0·5 µg, 2·5 µg, or 5·0 µg of the non-adjuvanted investigational vaccine (for each serotype), or placebo. All study participants and study staff not involved with vaccine preparation were masked to the randomisation group. The vaccine contained an equal dose (0·5 µg, 2·5 µg, 5·0 µg, or 20 µg) of each of three glycoconjugates (serotypes Ia, Ib and III). Reactogenicity was monitored to day 7 and unsolicited adverse events (adverse events) and infant safety were recorded throughout the study. The primary outcomes were tolerability and GBS-specific antibody response (measured as geometric mean concentrations [GMCs] in µg/mL) following the two injections for cohort 1, and selection of one vaccine dose based on analysis of serotype-specific antibody responses at delivery (+72 h) for use in subsequent studies. These outcomes were assessed in participants or infants of participants who correctly received the study vaccine with no major protocol deviations, and provided evaluable serum samples at day 1 and the scheduled timepoints throughout the study. This study is registered with ClinicalTrials.gov, NCT01193920. FINDINGS: Between Oct 5, 2010, and Sept 21, 2011, we screened 75 non-pregnant and 417 pregnant healthy South African women. Of these, 60 non-pregnant women were enrolled in cohort 1 (40 randomly assigned to the GBS 20 µg group and 40 randomly assigned to the placebo group) and 320 pregnant women were enrolled in cohort 2 (80 in each of the four groups). Among the randomised groups of pregnant women, 33-40% experienced at least one local and 54-71% one systemic solicited adverse event, less than 4% of which were severe, and the rate did not differ by study group. Also, 2% of the pregnancies resulted in stillbirth and 3·5% of the liveborn babies died by 12 months age, none of these deaths were attributed to vaccination. There was one death in a GBS-vaccine recipient, which too was unrelated to vaccination. For cohort 1, serotype-specific antibody concentrations were significantly higher, as evident by no overlap of the 95% CIs of GMCs against all three serotypes in the vaccinated group than the placebo group. For cohort 2, pregnant women in all vaccine groups had significantly higher GMCs than did those in the placebo group at delivery (eg, GMCs against serotype Ia were 11 µg/mL [95% CI 7·0-18] for the GBS vaccine 0·5 µg group, 18 µg/mL [11-29] for the GBS vaccine 2·5 µg group, 22 µg/mL [13-35] for the GBS vaccine 5·0 µg group, and 0·64 µg/mL [0·42-0·98] for the placebo group) and at all measured timepoints. GMCs did not differ significantly between the vaccine doses at any of the measured timepoints (p>0·05). INTERPRETATION: The vaccine was well tolerated and induced capsular-specific antibody responses, in non-pregnant and pregnant women. Maternal vaccination led to higher GBS serotype-specific antibody concentrations in infants than did placebo, with both interventions resulting in similar safety profiles. FUNDING: Novartis Vaccines and Diagnostics division, now part of the GlaxoSmithKline group of companies.

Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2.

The sleep disorder narcolepsy is linked to the HLA-DQB1*0602 haplotype and dysregulation of the hypocretin ligand-hypocretin receptor pathway. Narcolepsy was associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic. In contrast, very few cases were reported after Focetria vaccination (a differently manufactured adjuvanted influenza pandemic vaccine). We hypothesized that differences between these vaccines (which are derived from inactivated influenza viral proteins) explain the association of narcolepsy with Pandemrix-vaccinated subjects. A mimic peptide was identified from a surface-exposed region of influenza nucleoprotein A that shared protein residues in common with a fragment of the first extracellular domain of hypocretin receptor 2. A significant proportion of sera from HLA-DQB1*0602 haplotype-positive narcoleptic Finnish patients with a history of Pandemrix vaccination (vaccine-associated narcolepsy) contained antibodies to hypocretin receptor 2 compared to sera from nonnarcoleptic individuals with either 2009 A(H1N1) pandemic influenza infection or history of Focetria vaccination. Antibodies from vaccine-associated narcolepsy sera cross-reacted with both influenza nucleoprotein and hypocretin receptor 2, which was demonstrated by competitive binding using 21-mer peptide (containing the identified nucleoprotein mimic) and 55-mer recombinant peptide (first extracellular domain of hypocretin receptor 2) on cell lines expressing human hypocretin receptor 2. Mass spectrometry indicated that relative to Pandemrix, Focetria contained 72.7% less influenza nucleoprotein. In accord, no durable antibody responses to nucleoprotein were detected in sera from Focetria-vaccinated nonnarcoleptic subjects. Thus, differences in vaccine nucleoprotein content and respective immune response may explain the narcolepsy association with Pandemrix.

A cell culture-derived MF59-adjuvanted pandemic A/H7N9 vaccine is immunogenic in adults.

A potentially deadly A/H7N9 avian-origin influenza virus is currently the cause of an ongoing outbreak in China. Preparedness plans have thus been initiated to preempt the spread of this virus, which appears to have substantial pandemic potential. To effectively prevent a pandemic from unfolding, rapid production of an immunogenic vaccine with an acceptable safety profile is critical. Given the significance to public health, we are reporting immunogenicity and safety results from a phase 1 study in healthy adults administered one of four inactivated A/H7N9 vaccine formulations. Three formulations contained increasing quantities of antigen and of an oil-in-water adjuvant, MF59, and one formulation contained only the maximum dose of antigen without adjuvant. All vaccine formulations were derived using a synthetic virus seed technology in combination with a cell culture approach; together, these techniques have been shown to expedite vaccine production compared to conventional methods. Higher responses were seen with the MF59-adjuvanted versus the nonadjuvanted A/H7N9 vaccine, with significant and potentially protective immune responses after two doses in most subjects with no preexisting immunity to the H7N9 virus. Further, despite increased injection site pain and other mild effects with MF59, all formulations were well tolerated. These encouraging immunogenicity and safety data on the A/H7N9 vaccine provide a strong rationale for further clinical development. By also using synthetic seed/cell culture technology, we are now one step closer to being able to rapidly and reliably respond to a potential H7N9 pandemic using a clinically tested A/H7N9 vaccine.

Comparison of the safety and immunogenicity of an MF59®-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects.

AIM: Adjuvanted influenza vaccines can overcome the poor antibody response of conventional non-adjuvanted vaccines in the elderly. We evaluated the immunogenicity, safety and clinical effectiveness of an MF59(®)-adjuvanted trivalent influenza vaccine (aTIV) compared with a non-adjuvanted vaccine (TIV) in subjects ≥65 years old, with or without co-morbidities. METHODS: In 2010-2011, subjects (N=7082) were randomized to receive one dose of aTIV or TIV. Co-primary objectives were to assess lot-to-lot consistency of aTIV, non-inferiority, superiority and immunogenicity 22 days after vaccination. Clinical effectiveness, reactogenicity and serious adverse events were monitored up to Day 366. RESULTS: The immunological equivalence of three lots of aTIV was demonstrated. aTIV was not only non-inferior to TIV but also elicited significantly higher antibody responses at Day 22 than TIV against all homologous and heterologous strains, even in subjects with co-morbidities. Superiority was not established. Reactogenicity was higher in the aTIV group, but reactions were mild to moderate and transient. CONCLUSIONS: aTIV elicited a significantly higher antibody response than TIV, especially against A/H3N2 strains, although superiority by pre-defined criteria was not formally met. The study demonstrates potential immunological benefits of MF59-adjuvanted influenza vaccines for the elderly. This trial was registered with www.clinicaltrials.gov (NCT01162122).

Prevention of group B streptococcal disease in the first 3 months of life: would routine maternal immunization during pregnancy be cost-effective?

BACKGROUND: A vaccine against group B streptococcus (GBS) that is intended for routine maternal immunization during pregnancy is in clinical development. Addition of vaccination to screening and intrapartum antibiotic prophylaxis (IAP) may further reduce the burden of GBS disease in infancy; its potential cost-effectiveness is unknown, however. METHODS: We evaluated the cost-effectiveness of routine immunization at week 28 of pregnancy with the trivalent GBS (serotypes Ia, Ib and III) vaccine that is in clinical development. The vaccine was assumed to be used in addition to screening and IAP, and reduce the risk of invasive infection in infancy due to covered serotypes. We estimated the effectiveness of immunization in terms of additional cases of GBS disease prevented, deaths averted, life-years saved, and quality-adjusted life-years (QALYs) gained; potential reductions in prematurity and stillbirths were not considered. Costs considered included those of acute care for infants with GBS disease, and chronic care for those with long-term disability. The cost of immunization was assumed to be $100 per person. RESULTS: Assuming 85% coverage, routine maternal immunization against GBS added to screening and IAP would prevent an additional 899 cases of GBS disease and an additional 35 deaths among infants in the US. The total annual cost of immunization would be $362.7 million; estimated cost savings from prevention of GBS disease in infancy would be $43.5 million. The cost-effectiveness of immunization was estimated to be $91,321 per QALY gained. Findings were sensitive to assumptions regarding vaccine efficacy and cost. CONCLUSIONS: Addition of a trivalent GBS maternal vaccine to screening and IAP might further reduce the burden of GBS disease among infants in the US, and may be comparable in cost-effectiveness to other vaccines recently approved for use in children and adolescents.

Enhanced and persistent antibody response against homologous and heterologous strains elicited by a MF59-adjuvanted influenza vaccine in infants and young children.

BACKGROUND: Non-adjuvanted seasonal influenza vaccines show only modest efficacy in young children. This study compared the immunogenicity, reactogenicity and safety of the MF59-adjuvanted trivalent subunit vaccine (aTIV) with two non-adjuvanted trivalent vaccines, TIV-1, the non-adjuvanted version of aTIV, and TIV-2, a split virion vaccine. METHODS: 6078 children received two doses of aTIV (n=3125), TIV-1 (n=1479), or TIV-2 (n=1474) four weeks apart (Days 1 and 29). Children aged 6 to <36 months and 36 to <72 months received 0.25 mL and 0.50 mL doses, respectively. Immunogenicity was assessed by hemagglutination inhibition (HI) assay (n=2435) on Days 1, 29, 50 and 209. Safety was assessed up to Day 394. RESULTS: After the second vaccination (Day 50), the aTIV group showed significantly higher geometric mean HI titers and seroconversion rates than the TIV-1 or TIV-2 groups against all homologous and heterologous strains. The difference was enhanced at HI titers ≥110. aTIV elicited a faster, more persistent antibody response, with significantly higher titers in the aTIV group after one vaccination (Day 29) and after six months (Day 209) than in either TIV group. aTIV was more reactogenic than were TIV-1 and TIV-2 but rates of severe adverse events were very low for all three vaccines. CONCLUSION: In infants and young children, the MF59-adjuvanted vaccine induced substantially faster (after one dose), higher, persistent HI titers than the non-adjuvanted vaccines, with consistently higher seroprotection rates at increased threshold HI titers. This trial is registered at clinicaltrials.gov: NCT01346592.