The efficacy of a novel vaccine against influenza virus A (H1N1) in patients with hematologic malignancies is largely unknown.
We prospectively evaluated the humoral and cellular immune responses after one injection of monovalent adjuvanted 2009 H1N1 vaccine in 47 adults with hematologic malignancies and 77 controls by hemagglutination-inhibition assay and flow-cytometry analysis on day 0, 28, 50, and 90.
On day 28 postvaccination, patients had lower seroprotection (95.2% vs. 75.2%, P < 0.01) and seroconversion (88.7% vs. 51.1%, P < 0.01) rates, as well as geometric mean titer (GMT; 256 vs. 134, P < 0.05), relative to controls. Response to vaccination varied according to the evaluated time point and the patient status: Patients not receiving chemotherapy had seroprotection and GMTs similar to controls in all time points, while patients receiving chemotherapy or allogeneic hematopoietic stem cell transplant (HSCT) had lower seroprotection and seroconversion levels than controls on day 28 and 50. EMEA cutoffs for efficacy were reached from day 28 by patients in follow-up or under treatment and only from day 90 by those with HSCT, especially if still under immunosuppressants. Patients treated with immunomodulatory drugs had higher antibody responses in terms of seroprotection and GMTs. T- and NK cell-mediated responses mounted from day 50 and did not differ between patients and controls.
According to EMEA recommendation, H1N1 vaccination strategy was effective at protecting most of the hematologic patients, but needed to be improved in those more immunocompromised.
"To determine the efficacy of MB as an adjuvant in eliciting an extended systemic and mucosal immune response, a parallel treatment study was conducted for 16 weeks (twice the length of the first study) and a time point used to evaluate long-term antibody responses , , , . Study #2 contained four vaccination groups consisting of NV VLP (25 µg) delivered IN with a high dose of MB (200 µg) (n = 7), VLP (25 µg) with GARD (25 µg), VLP alone (25 µg) (n = 7 ), or PBS control- vaccinated delivery of PBS (n = 7). "
[Show abstract][Hide abstract] ABSTRACT: Murabutide (MB) is a synthetic immunomodulator recognized by the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) receptor on mammalian cells. MB has previously been approved for testing in multiple human clinical trials to determine its value as an antiviral therapeutic, and as an adjuvant for injected vaccines. We have found a new use for this immunomodulator; it functions as a mucosal adjuvant that enhances immunogenicity of virus-like particles (VLP) administered intranasally. MB enhanced Norwalk virus (NV) VLP-specific IgG systemically and IgA production at distal mucosal sites following intranasal (IN) vaccination. A dose escalation study identified 100 µg as the optimal MB dosage in mice, based on the magnitude of VLP-specific IgG, IgG1, IgG2a and IgA production in serum and VLP-specific IgA production at distal mucosal sites. IN vaccination using VLP with MB was compared to IN delivery VLP with cholera toxin (CT) or gardiquimod (GARD) and to parenteral VLP delivery with alum; the MB groups were equivalent to CT and GARD and superior to alum in inducing mucosal immune responses and stimulated equivalent systemic VLP-specific antibodies. These data support the further testing of MB as a potent mucosal adjuvant for inducing robust and durable antibody responses to non-replicating subunit vaccines.
PLoS ONE 07/2012; 7(7):e41529. DOI:10.1371/journal.pone.0041529 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT This is a randomized trial evaluating the safety and immunogenicity of one or two doses of 2009 pandemic H1N1 influenza vaccination in adults with lymphoid malignancies. Adults with a lymphoid malignancy receiving active systemic therapy, or within a year after autologous stem cell transplantation received one dose of AS03-adjuvanted A/California/7/2009(H1N1) vaccine, and randomized 21 days later to a second dose or no further vaccination. The primary outcomes were seroprotection and seroconversion rates by hemagglutination inhibition 21 and 42 days after initial vaccination. Twenty-two patients received one dose, and 20 patients received a second dose. Seroconversion rates at day 21 were 30% (one dose) and 5% (two doses), and subsequently 30% for both groups at day 42. Seroprotection rates at day 21 were 40% (one dose) and 15% (two doses), and subsequently 35% (one dose) and 40% (two doses) at day 42. Differences in serologic endpoints were not statistically significant between both study arms at day 42. Patients with low levels of B-cells (CD19-positive) had low seroconversion rates on days 21 (OR 0.74, 95% CI 0.59-0.93, p=0.043) and 42 (OR 0.12, 95% CI 0.01-1.07, p=0.058). Only 3 of the 14 patients who received rituximab achieved seroprotective titers by day 42. Patients with lymphoid malignancies did not achieve rates of seroconversion or seroprotection seen in healthy subjects despite a second dose and the use of an adjuvant. Notwithstanding suboptimal immunogenicity, seasonal and pandemic influenza vaccination should continue to be recommended.
[Show abstract][Hide abstract] ABSTRACT: Influenza, known as the ‘flu’, is a recurrent acute viral infection that might cause severe
inflammation, particularly in vulnerable individuals, i.e. young children, the elderly, and
immune-suppressed patients, such as stem cell transplant recipients. Prevention strategies,
primarily vaccination, and possibly the use of anti-viral drugs, are recommended with the aim
to reduce mortality and morbidity. Influenza vaccination responses are often sub-optimal in
immune-compromised patients. There is therefore a need to evaluate other vaccination
systems and schedules to improve vaccine efficacy.
We mapped the humoral and cellular anti-flu directed immune responses and studied in a first
set of experiments the immune responses in immune competent individuals prior to, and
following a natural pandemic influenza infection, as well as after adjuvanted Pandemrix®
influenza vaccination. This was performed prospectively during the H1N1 pandemic
influenza of 2009. ‘High content’ influenza proteome peptide arrays were used to gauge
serum IgG epitope signatures prior to and after Pandemrix® vaccination/ or H1N1 pandemic
infection described in paper I. A novel epitope residing in the sialic acid receptor-binding
domain of VEPGDKITFEATGNL (251-265) of the pandemic flu hemagglutinin was
identified. This epitope was found to be exclusively recognized in serum from previously
vaccinated individuals and never in serum from individuals with H1N1 infection. The natural
H1N1 infection induced a different footprint of IgG epitope recognition patterns as compared
to the Pandemrix® H1N1 vaccination.
Pre-transplant influenza vaccination of the donor or allogeneic hematopoietic stem cell
(HSCT) candidate was evaluated in a randomized study of 122 HSCT patients reported in
paper II. The antibody titers against H1 (p=0.028) and H3 (p<0.001) were highest in the pretransplant recipient vaccination group until d.180 after transplantation. A significant
difference was found concerning the specific Ig levels against pandemic H1N1 at 6 months
after HSCT (p=0.02). The mean IgG levels against pandemic H1N1, generic H1N1 and
H3N2 were highest in the pre-transplant recipient vaccination group. Pre-transplant influenza
vaccination of the donor or the HSCT candidate was found to be beneficial in eliciting
The immunogenicity after a single dose of adjuvanted trivalent virosomal vaccination was
evaluated in a cohort of 21 HSCT recipients and compared to a control cohort of 30 HSCT
recipients who received a single dose of non-adjuvanted seasonal trivalent subunit
vaccination, reported in Paper III. The delta change of IFNγ production in response to
pandemic influenza H1N1 (p=0.005) and influenza B antigens (p=0.01) were significantly
increased in blood from individuals who received the virosomal, as compared to the nonadjuvanted vaccine. Virosomal vaccination was found to be beneficial in eliciting robust
cellular immune responses to influenza pandemic H1N1.
Pandemic influenza hemagglutinin MHC class 1 peptide restricted CD8 T-cells were
enumerated over the course of a natural pandemic influenza infection and Pandemrix®
vaccination in a prospective study reported in Paper IV. PBMCs from vaccinated control
individuals exhibited a significantly increased percentage of (p=0.003) hemagglutinin
specific CD8 T-cells that resided in the terminally differentiated effector memory
compartment, as compared to PBMCs from individuals that contracted H1N1 infection. The
cellular immune signatures were found to be different elicited by a natural flu infection as
compared to vaccination concerning the phenotype/maturation of antigen-specific CD8 Tcells.
05/2015, Degree: Doctoral Thesis, Supervisor: Prof. Per Ljungman and Prof. Markus Maeurer
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