Dimitar Sajkov

Randomized clinical trial of immunogenicity and safety of a recombinant H1N1/2009 pandemic influenza vaccine containing Advax™ polysaccharide adjuvant.

BACKGROUND Timely vaccine supply is critical during influenza pandemics. A recombinant hemagglutinin (rHA)-based vaccine could overcome production hurdles of egg-based vaccines but has never previously been tested in a real-life pandemic setting. The primary aim was to determine the efficacy of a recombinant pandemic vaccine and whether its immunogenicity could be enhanced by a novel polysaccharide adjuvant (Advax™). METHODS 281 adults aged 18-70 years were recruited in a randomized, subject and observer blinded, parallel-group study of rHA H1N1/2009 vaccine with or without adjuvant. Immunizations were at 0 and 3 weeks with rHA 3, 11 or 45 μg. Serology and safety was followed for 6 months. RESULTS At baseline, only 9.1% of subjects (95% CI: 6.0-13.2) had seroprotective H1N1/2009 titers. Seroconversion rates varied by rHA dose, presence of adjuvant, subject age and number of immunizations. Eighty percent (95% CI: 52-96) of 18-49 year olds who received rHA 45 μg with adjuvant were seroprotected at week 3, representing a 11.1-fold increase in antibody titers from baseline. Advax™ adjuvant increased seroprotection rates by 1.9 times after the first, and 2.5 times after the second, immunization when compared to rHA alone. Seroprotection was sustained at 26 weeks and the vaccine was well tolerated with no safety issues. CONCLUSIONS The study confirmed the ability to design, manufacture, and release a recombinant vaccine within a short time from the start of an actual influenza pandemic. Advax™ adjuvant significantly enhanced rHA immunogenicity.

The COPD assessment test (CAT) assists prediction of COPD exacerbations in high-risk patients

UNLABELLED We evaluated the predictive value of the COPD assessment test (CAT™) for exacerbation in the following six months or time to first exacerbation among COPD patients with previous exacerbations. COPD outpatients with a history of exacerbation from 19 hospitals completed the CAT questionnaire and spirometry over six months. Exacerbation events were prospectively collected using a structured questionnaire. The baseline CAT score categorised into four groups (0-9, 10-19, 20-29, and 30-40) showed strong prediction for time to first exacerbation and modest prediction for any exacerbation or moderate-severe exacerbation (AUC 0.83, 0.64, and 0.63 respectively). In multivariate analyses, the categorised CAT score independently predicted all three outcomes (p = 0.001 or p < 0.001). Compared with the lowest CAT score category, the higher categories were associated with significantly shorter time to first exacerbation and higher exacerbation risks. The corresponding adjusted median time was >24, 14, 9, and 5 weeks and the adjusted RR was 1.00, 1.30, 1.37, and 1.50 in the category of 0-9, 10-19, 20-29, and 30-40 respectively. Exacerbation history (≥2 vs. 1 event in the past year) was related to time to first exacerbation (adjusted HR 1.35; p = 0.023) and any exacerbation during the study period (adjusted RR 1.15; p = 0.016). The results of this study support the use of the CAT as a simple tool to assist in the identification of patients at increased risk of exacerbations. This could facilitate timely and cost-effective implementation of preventive interventions, and improve health resource allocation. TRIAL REGISTRATION Clinicaltrials.gov: NCT01254032.

Delta Inulin Adjuvant Enhances Plasmablast Generation, Expression of Activation-Induced Cytidine Deaminase and B-Cell Affinity Maturation in Human Subjects Receiving Seasonal Influenza Vaccine

There is a major need for new adjuvants to improve the efficacy of seasonal and pandemic influenza vaccines. Advax is a novel polysaccharide adjuvant based on delta inulin that has been shown to enhance the immunogenicity of influenza vaccine in animal models and human clinical trials. To better understand the mechanism for this enhancement, we sought to assess its effect on the plasmablast response in human subjects. This pilot study utilised cryopreserved 7 day post-vaccination (7dpv) peripheral blood mononuclear cell samples obtained from a subset of 25 adult subjects from the FLU006-12 trial who had been immunized intramuscularly with a standard dose of 2012 trivalent inactivated influenza vaccine (TIV) alone (n=9 subjects) or combined with 5mg (n=8) or 10mg (n=8) of Advax adjuvant. Subjects receiving Advax adjuvant had increased 7dpv plasmablasts, which in turn exhibited a 2-3 fold higher rate of non-silent mutations in the B-cell receptor CDR3 region associated with higher expression of activation-induced cytidine deaminase (AID), the major enzyme controlling BCR affinity maturation. Together, these data suggest that Advax adjuvant enhances influenza immunity in immunized subjects via multiple mechanisms including increased plasmablast generation, AID expression and CDR3 mutagenesis resulting in enhanced BCR affinity maturation and increased production of high avidity antibody. How Advax adjuvant achieves these beneficial effects on plasmablasts remains the subject of ongoing investigation. Trial Registration Australia New Zealand Clinical Trials Register ACTRN12612000709842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362709

Management of dyspnea in advanced pulmonary arterial hypertension

Purpose of reviewPulmonary hypertension leads to progressive increase in pulmonary vascular resistance, heart failure, and death. Pulmonary arterial hypertension (PAH) is a subset of pulmonary hypertension affecting small pulmonary arteries and not associated with underlying heart or lung disease. Dyspnea and exercise intolerance are hallmarks of PAH and are used to monitor disease progression. This review focuses on recent advances in the pathophysiology and treatment of dyspnea in PAH. Recent findingsThe etiological classification of pulmonary hypertension and World Health Organization functional class clinical classification, as used to guide management, have recently been revised. Dyspnea and PAH disease progression are best assessed by cardiopulmonary exercise testing and the six-minute walk test. Understanding of the molecular pathogenesis of PAH has led to new classes of treatments, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Prostanoids have the longest track record in treatment of PAH but a short half-life and cumbersome delivery systems limit their utility. More convenient endothelin receptor antagonists are becoming mainstream in PAH management. Phosphodiesterase-5 inhibitors improve exercise capacity and quality of life, although long-term outcome data are pending. Combination therapy with different medication classes appears promising for progressive disease. SummaryEstablishing the cause and clinical severity of pulmonary hypertension is critical for management. The pathophysiology of dyspnea in PAH is complex and related to pulmonary vascular resistance. Although disease-specific treatments are now available, a cure for PAH remains elusive and trials of combination treatments to improve symptoms and outcomes are ongoing.

Human Phase 1 trial of low-dose inactivated seasonal influenza vaccine formulated with Advax™ delta inulin adjuvant

Abstract Influenza vaccines are usually non-adjuvanted but addition of adjuvant may improve immunogenicity and permit dose-sparing, critical for vaccine supply in the event of an influenza pandemic. The aim of this first-in-man study was to determine the effect of delta inulin adjuvant on the safety and immunogenicity of a reduced dose seasonal influenza vaccine. Healthy male and female adults aged 18–65years were recruited to participate in a randomized controlled study to compare the safety, tolerability and immunogenicity of a reduced-dose 2007 Southern Hemisphere trivalent inactivated influenza vaccine formulated with Advax™ delta inulin adjuvant (LTIV+Adj) when compared to a full-dose of the standard TIV vaccine which does not contain an adjuvant. LTIV+Adj provided equivalent immunogenicity to standard TIV vaccine as assessed by hemagglutination inhibition (HI) assays against each vaccine strain as well as against a number of heterosubtypic strains. HI responses were sustained at 3months post-immunisation in both groups. Antibody landscapes against a large panel of H3N2 influenza viruses showed distinct age effects whereby subjects over 40years old had a bimodal baseline HI distribution pattern, with the highest HI titers against the very oldest H3N2 isolates and with a second HI peak against influenza isolates from the last 5–10years. By contrast, subjects >40years had a unimodal baseline HI distribution with peak recognition of H3N2 isolates from approximately 20years ago. The reduced dose TIV vaccine containing Advax adjuvant was well tolerated and no safety issues were identified. Hence, delta inulin may be a useful adjuvant for use in seasonal or pandemic influenza vaccines. Australia New Zealand Clinical Trial Registry: ACTRN12607000599471

Pediatric influenza immunization

The recent H1N1 2009 pandemic provided an opportunity to reflect on current inf luenza immunization practices in children and future directions in this field. While the elderly suffer the vast burden of seasonal influenza morbidity and mortality, there is also an increased disease burden in very young children, a population in which approximately 1–5% of influenza deaths occur [1]. An Australian study reported a mean hospital admission rate with influenza-associated illness in children 0–4 years of age of 49.5 per 100,000, comparable to the rate of 52 per 100,000 in people over 85 years [2]. Thus, although inf luenza mortality rates are much lower in children than the elderly, the converse is true of hospitalization rates. One reason for the increased disease burden of influenza in young children is that the frequency of influenza infection is much higher in children than in any other age group. Children, as a group, are more susceptible to infection as many are immunologically naive to influenza viruses. This, combined with their notoriously poor hygiene and their concentration in institutions such as daycare and schools, makes them an ideal vector for viral transmission. Serological data from Hong Kong early in the 2009 H1N1 pandemic showed that 43.4% of school children 5–14 years of age had seroconverted consistent with having been infected, compared with a seroconversion rate of just 4.6% in those 30–59 years of age [3]. When hospitalization or death was corrected for the higher infection rate in children, adults aged 50–59 years had a 9.5-times higher risk if infected of intensive care unit admission and 66-times higher risk of death than children [3].

Panblok-H1+advax H1N1/2009pdm vaccine: Insights into rapid development of a delta inulin adjuvanted recombinant pandemic influenza vaccine

ABSTRACT Timely vaccine supply is critical during influenza pandemics but is impeded by current virus-based manufacturing methods. The 2009 H1N1/2009pdm ‘swine flu’ pandemic reinforced the need for innovation in pandemic vaccine design. We report on insights gained during rapid development of a pandemic vaccine based on recombinant haemagglutinin (rHA) formulated with Advax™ delta inulin adjuvant (Panblok-H1/Advax). Panblok-H1/Advax was designed and manufactured within 1 month of the pandemic declaration by WHO and successfully entered human clinical testing in under 3 months from first isolation and sequencing of the novel pandemic virus, requiring several major challenges to be overcome. Panblok-H1/Advax successfully induced neutralising antibodies against the pandemic strain, but also induced cross-neutralising antibodies in a subset of subjects against an H1N1 strain (A/Puerto Rico/8/34) derived from the 1918 Spanish flu, highlighting the possibility to use Advax to induce more broadly cross-protective antibody responses. Interestingly, the rHA from H1N1/2009pdm exhibited variants in the receptor binding domain that had a major impact on receptor binding and hemagglutination ability. We used an in silico structural modeling approach to better understand the unusual behavior of the novel hemagglutinin, thereby demonstrating the power of computational modeling approaches for rapid characterization of new pandemic viruses. While challenges remain in ensuring ultrafast vaccine access for the entire population in response to future pandemics, the adjuvanted recombinant Panblok-H1/Advax vaccine proved its utility during a real-life pandemic situation.

Dyspnea in Pulmonary Arterial Hypertension

Dyspnea is a complex sensation involving interaction of physiological, psychological, social, and environmental factors. Dyspnea in general is common across cardio-vascular and respiratory conditions and it is often difficult to clinically differentiate the exact cause of dyspnea in patients with heart or lung disease. Pulmonary hypertension in the absence of heart or lung disease, a condition called pulmonary arterial hypertension (PAH), is due to endothelial dysfunction and remodelling of small pulmonary arteries. Progressive dyspnea on exertion is a cardinal sign of PAH, which is often first diagnosed when in advanced stages. Improved understanding of pathogenic mechanisms underlying PAH and the related dyspnea should translate into new treatment options for symptom control and to prevent disease progression. This chapter reviews the current understanding of the etiology and pathogenesis of PAH and recent advances in management of this debilitating condition.