Lessons from pandemic influenza A(H1N1): The research-based vaccine industry's perspective

AbstractAs A(H1N1) influenza enters the post-pandemic phase, health authorities around the world are reviewing the response to the pandemic. To ensure this process enhances future preparations, it is essential that perspectives are included from all relevant stakeholders, including vaccine manufacturers. This paper outlines the contribution of R&D-based influenza vaccine producers to the pandemic response, and explores lessons that can be learned to improve future preparedness.The emergence of 2009 A(H1N1) influenza led to unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade.During this period, manufacturers greatly increased influenza vaccine production capacity, and estimates suggest a further doubling of capacity by 2014. Producers also introduced cell-culture technology, while adjuvant and whole virion technologies significantly reduced pandemic vaccine antigen content. This substantially increased pandemic vaccine production capacity, which in July 2009 WHO estimated reached 4.9 billion doses per annum. Manufacturers also worked with health authorities to establish risk management plans for robust vaccine surveillance during the pandemic. Individual producers pledged significant donations of vaccine doses and tiered-pricing approaches for developing country supply.Based on the pandemic experience, a number of improvements would strengthen future preparedness. Technical improvements to rapidly select optimal vaccine viruses, and processes to speed up vaccine standardization, could accelerate and extend vaccine availability. Establishing vaccine supply agreements beforehand would avoid the need for complex discussions during a period of intense time pressure.Enhancing international regulatory co-operation and mutual recognition of approvals could accelerate vaccine supply, while maintaining safety standards. Strengthening communications with the public and healthcare workers using new approaches and new channels could help improve vaccine uptake. Finally, increasing seasonal vaccine coverage will be particularly important to extend and sustain pandemic vaccine production capacity

Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading?

Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre- and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P<.0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P<.0005), pre- and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P=.001) and hepcidin (P=.001). No correlation of pre- or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre- and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT

Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading?

Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre-and post-HCT was present in all patients. Median hepcidin pre-and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P &lt; .0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P &lt; .0005), pre-and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P = .001) and hepcidin (P = .001). No correlation of pre-or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre-and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT

Vaccines for Pandemic Influenza

A program to develop vaccines to prevent avian influenza pandemics is under way.Vaccines for Pandemic Influenz

Vaccines and Antiviral Drugs in Pandemic Preparedness

Controlling a pandemic with vaccine and antiviral drugs will require a coordinated international approach to determine how the least amount of virus can immunize the largest segment of a population

Immunogenicity Profile of a 3.75-μg Hemagglutinin Pandemic rH5N1 Split Virion AS03A-Adjuvanted Vaccine in Elderly Persons: A Randomized Trial

Background. Elderly persons often experience a reduced immune response to influenza vaccination. We evaluated the usual dose of AS03A-adjuvanted H5N1 pandemic vaccine (3.75 μg hemagglutinin of A/Vietnam/1194/2004-like strain) compared with a double dose in an elderly population

Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older

BACKGROUND: The effectiveness of trivalent influenza vaccines may be reduced in older versus younger adults because of age-related immunosenescence. The use of an adjuvant in such a vaccine is one strategy that may combat immunosenescence, potentially by bolstering T-cell mediated responses. METHODS: This observer-blind study, conducted in the United States (US) and Spain during the 2008-2009 influenza season, evaluated the effect of Adjuvant System AS03 on specific T-cell responses to a seasonal trivalent influenza vaccine (TIV) in >/=65 year-old adults.Medically-stable adults aged >/=65 years were randomly allocated to receive a single dose of AS03-adjuvanted TIV (TIV/AS03) or TIV. Healthy adults aged 18-40 years received only TIV. Blood samples were collected on Day 0, Day 21, Day 42 and Day 180. Influenza-specific CD4+ T cells, defined by the induction of the immune markers CD40L, IL-2, IFN-gamma, or TNF-alpha, were measured in ex vivo cultures of antigen-stimulated peripheral blood mononuclear cells. RESULTS: A total of 192 adults were vaccinated: sixty nine and seventy three >/=65 year olds received TIV/AS03 and TIV, respectively; and fifty 18 - 40 year olds received TIV. In the >/=65 year-old group on Day 21, the frequency of CD4+ T cells specific to the three vaccine strains was superior in the TIV/AS03 recipients to the frequency in TIV (p /=65 year-old recipients of TIV/AS03 than in the 18 - 40 year old recipients of TIV on Days 21 (p = 0.006) and 42 (p = 0.011). CONCLUSION: This positive effect of AS03 Adjuvant System on the CD4+ T-cell response to influenza vaccine strains in older adults could confer benefit in protection against clinical influenza disease in this population. TRIAL REGISTRATION: (Clinicaltrials.gov.). NCT00765076

A phase II, open-label, multicentre study to evaluate the immunogenicity and safety of an adjuvanted prepandemic (H5N1) influenza vaccine in healthy Japanese adults

<p>Abstract</p> <p>Background</p> <p>Promising clinical data and significant antigen-sparing have been demonstrated for a pandemic H5N1 influenza split-virion vaccine adjuvanted with AS03_A, an α-tocopherol-containing oil-in-water emulsion-based Adjuvant System. Although studies using this formulation have been reported, there have been no data for Japanese populations. This study therefore aimed to assess the immunogenicity and tolerability of a prepandemic (H5N1) influenza vaccine adjuvanted with AS03_Ain Japanese adults.</p> <p>Methods</p> <p>This open-label, single-group study was conducted at two centres in Japan in healthy Japanese males and females aged 20-64 years (n = 100). Subjects received two doses of vaccine, containing 3.75 μg haemagglutinin of the A/Indonesia/5/2005-like IBCDC-RG2 Clade 2.1 (H5N1) strain adjuvanted with AS03_A, 21 days apart. The primary endpoint evaluated the humoral immune response in terms of H5N1 haemagglutination inhibition (HI) antibody titres against the vaccine strain (Clade 2.1) 21 days after the second dose. Ninety five percent confidence intervals for geometric mean titres, seroprotection, seroconversion and seropositivity rates were calculated. Secondary and exploratory endpoints included the assessment of the humoral response in terms of neutralising antibody titres, the response against additional H5N1 strains (Clade 1 and Clade 2.2), as well as the evaluation of safety and reactogenicity.</p> <p>Results</p> <p>Robust immune responses were elicited after two doses of the prepandemic influenza vaccine adjuvanted with AS03_A. Overall, vaccine HI seroconversion rates and seroprotection rates were 91% 21 days after the second vaccination. This fulfilled all regulatory acceptance criteria for the vaccine-homologous HI antibody level. A substantial cross-reactive humoral immune response was also observed against the virus strains A/turkey/Turkey/1/2005 (Clade 2.2) and A/Vietnam/1194/2004 (Clade 1) after the second vaccine administration. A marked post-vaccination response in terms of neutralising antibody titres was demonstrated and persistence of the immune response was observed 6 months after the first dose. The vaccine was generally well tolerated and there were no serious adverse events reported.</p> <p>Conclusions</p> <p>The H5N1 candidate vaccine adjuvanted with AS03_Aelicited a strong and persistent immune response against the vaccine strain A/Indonesia/5/2005 in Japanese adults. Vaccination with this formulation demonstrated a clinically acceptable reactogenicity profile and did not raise any safety concerns in this population.</p> <p>Trial registration</p> <p>Clinicaltrials.gov NCT00742885</p

Broad Clade 2 Cross-Reactive Immunity Induced by an Adjuvanted Clade 1 rH5N1 Pandemic Influenza Vaccine

The availability of H5N1 vaccines that can elicit a broad cross-protective immunity against different currently circulating clade 2 H5N1 viruses is a pre-requisite for the development of a successful pre-pandemic vaccination strategy. In this regard, it has recently been shown that adjuvantation of a recombinant clade 1 H5N1 inactivated split-virion vaccine with an oil-in-water emulsion-based adjuvant system also promoted cross-immunity against a recent clade 2 H5N1 isolate (A/Indonesia/5/2005, subclade 2.1). Here we further analyse the cross-protective potential of the vaccine against two other recent clade 2 isolates (A/turkey/Turkey/1/2005 and A/Anhui/1/2005 which are, as defined by WHO, representatives of subclades 2.2 and 2.3 respectively).Two doses of the recombinant A/Vietnam/1194/2004 (H5N1, clade 1) vaccine were administered 21 days apart to volunteers aged 18-60 years. We studied the cross-clade immunogenicity of the lowest antigen dose (3.8 microg haemagglutinin) given with (N = 20) or without adjuvant (N = 20). Immune responses were assessed at 21 days following the first and second vaccine doses and at 6 months following first vaccination. Vaccination with two doses of 3.8 microg of the adjuvanted vaccine induced four-fold neutralising seroconversion rates in 85% of subjects against A/turkey/Turkey/1/2005 (subclade 2.2) and 75% of subjects against A/Anhui/1/2005 (subclade 2.3) recombinant strains. There was no response induced against these strains in the non-adjuvanted group. At 6 months following vaccination, 70% and 60% of subjects retained neutralising antibodies against the recombinant subclade 2.2 and 2.3 strains, respectively and 40% of subjects retained antibodies against the recombinant subclade 2.1 A/Indonesia/5/2005 strain.In addition to antigen dose-sparing, adjuvantation of inactivated split H5N1 vaccine promotes broad and persistent cross-clade immunity which is a pre-requisite for a pre-pandemic vaccine.ClinicalTrials.gov NCT00309634