Publications by authors named "Maria Lattanzi"

29 Publications

  • Page 1 of 1

Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in pregnant women and their infants: Results from a randomized placebo-controlled phase II trial.

Vaccine 2020 10 1;38(44):6930-6940. Epub 2020 Sep 1.

GSK, Rockville, MD, USA. Electronic address:

Background: This study evaluated the safety and immunogenicity of an investigational trivalent group B streptococcus (GBS) vaccine in US pregnant women, transplacental serotype-specific antibody transfer and persistence in infants, and serotype-specific antibodies in breast milk.

Methods: This randomized, observer-blind, placebo-controlled trial administered one dose of trivalent GBS vaccine (n = 49) or placebo (n = 26) to healthy pregnant 18-40-year-old women at 24-34 weeks' gestation. Women were enrolled from March 2014 to August 2015. Safety follow-up continued through postpartum day 180. Primary immunogenicity objectives were to evaluate serotype Ia/Ib/III-specific immunoglobulin G (IgG) levels in sera from women on day 1 (pre-vaccination), day 31, delivery and postpartum days 42 and 90, and from infants at birth (cord blood), days 42 and 90. Antibody transfer ratios (cord blood/maternal sera at delivery) and serotype-specific secretory immunoglobulin A (sIgA) and IgG in breast milk after delivery and on postpartum days 42 and 90 were evaluated. The planned sample size was not based on statistical assumptions for this descriptive study.

Results: Baseline characteristics were similar between groups. Serious adverse events were reported for 16% of GBS-vaccinated women and 15% of their infants, and 15% of placebo recipients and 12% of their infants; none were fatal or deemed vaccine-related. Serotype-specific IgG geometric mean concentrations (GMCs) were 13-23-fold higher in vaccine vs placebo recipients on day 31 and persisted until postpartum day 90. Median antibody concentrations were substantially higher in women with detectable pre-vaccination antibody concentrations. Antibody transfer ratios in the vaccine group were 0.62-0.82. Infant IgG GMCs and breast milk sIgA GMCs were higher in the vaccine vs the placebo group at all timepoints.

Conclusions: Maternal immunization with the trivalent GBS vaccine in US women had a favorable safety profile, elicited antibodies that were transplacentally transferred and persisted in infants for a minimum of 3 months.

Clinical Trial Registration: Clinicaltrials.gov, NCT02046148.
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http://dx.doi.org/10.1016/j.vaccine.2020.08.056DOI Listing
October 2020

Safety and immunogenicity of fully liquid and lyophilized formulations of an investigational trivalent group B streptococcus vaccine in healthy non-pregnant women: Results from a randomized comparative phase II trial.

Vaccine 2020 04 10;38(16):3227-3234. Epub 2020 Mar 10.

GSK, Rockville, MD, United States. Electronic address:

Background: We evaluated the safety and immunogenicity of liquid and lyophilized formulations of an investigational trivalent group B streptococcus (GBS) vaccine in non-pregnant women and assessed the formulations' equivalence in terms of serotype-specific immune response.

Methods: This phase II, randomized, comparative, observer-blind trial enrolled healthy non-pregnant women 18-40 years of age. Women received a single dose of fully liquid (n = 529) or lyophilized (n = 521) trivalent GBS vaccine on day 1. Safety assessments were performed up to day 181 (study termination). Serotype Ia/Ib/III-specific immunoglobulin G (IgG) antibodies were measured in sera from women on day 1 (pre-vaccination) and day 31. Equivalence between the two formulations was demonstrated if the two-sided 95% confidence interval (CI) for the ratio (liquid/lyophilized) of the geometric mean concentrations (GMCs) on day 31 was contained in a (0.5, 2.0) interval for each serotype.

Results: Solicited and unsolicited adverse events were reported at similar rates for both formulations. Serious adverse events were reported for six (1.1%) liquid GBS and nine (1.7%) lyophilized GBS vaccinated women, none of which were considered related to vaccination or fatal. On day 31, serotype-specific IgG concentrations were 8-16-fold higher than on day 1 in both groups. Equivalence of the liquid to the lyophilized formulation 30 days post-vaccination was demonstrated as the 95% CIs of the GMC ratios were within the pre-specified interval for the three serotypes: GMC ratios were 1.02 (95% CI: 0.79, 1.32) for serotype Ia, 0.93 (0.71, 1.21) for serotype Ib and 0.99 (0.76, 1.30) for serotype III.

Conclusions: Both formulations of the investigational trivalent GBS vaccine had favorable safety profiles and induced similar GBS serotype-specific antibody concentrations. This study demonstrated that the fully liquid formulation was equivalent to the lyophilized formulation in healthy non-pregnant women in terms of immunogenicity for all three serotypes.

Clinical Trials Registration: NCT02270944.
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http://dx.doi.org/10.1016/j.vaccine.2020.02.085DOI Listing
April 2020

MenACWY-CRM conjugate vaccine booster dose given 4-6 years after priming: Results from a phase IIIb, multicenter, open label study in adolescents and adults.

Vaccine 2019 09 5;37(42):6171-6179. Epub 2019 Sep 5.

GSK, Siena, Italy. Electronic address:

Background: Vaccination strategies against bacterial meningitis vary across countries. In the United States, a single dose of quadrivalent meningococcal conjugate vaccine (MenACWY) is recommended at 11-12 years of age, with a booster dose approximately 5 years later. We assessed immune responses to a booster dose of MenACWY-CRM vaccine after priming with MenACWY-CRM or MenACWY-D vaccines in adolescents and adults.

Methods: In this phase IIIb, multicenter, open-label study, healthy 15-55-year-olds, who received MenACWY-CRM (N = 301) or MenACWY-D (N = 300) 4-6 years earlier or were meningococcal vaccine-naïve (N = 100), received one MenACWY-CRM vaccine dose. Immunogenicity was evaluated pre-vaccination, 3 or 5 days post-vaccination (sampling subgroups), and 28 days post-vaccination by serum bactericidal activity assay using human complement (hSBA). After vaccination, participants were monitored for 7 days for reactogenicity, 29 days for unsolicited adverse events (AEs), and 181 days for serious AEs and medically-attended AEs.

Results: Sufficiency of the immune response to a MenACWY-CRM booster dose was demonstrated; the lower limit of the 1-sided 97.5% confidence interval for percentages of participants with hSBA seroresponse at 28 days post-vaccination was >75% for each serogroup in those primed with either the MenACWY-CRM or MenACWY-D vaccine. Seroresponse was observed in ≥93.24% of primed participants and ≥35.87% of naïve participants 28 days post-vaccination. At 5 days post-booster, among primed participants, hSBA titers ≥1:8 were achieved in ≥47.14% of participants for MenA and in ≥85.52% of participants for MenC, MenW and MenY, and 3.25- to 8.59-fold increases in hSBA geometric mean titers against each vaccine serogroup were observed. No safety concerns were raised throughout the 6-month follow-up period.

Conclusions: A booster dose of the MenACWY-CRM vaccine induced a robust and rapid anamnestic response in adolescents and adults, irrespectively of either MenACWY-CRM or MenACWY-D vaccine administered 4-6 years earlier, with an acceptable clinical safety profile. ClinicalTrials.gov registration: NCT02986854.
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http://dx.doi.org/10.1016/j.vaccine.2019.08.065DOI Listing
September 2019

Second five-year follow-up after a booster vaccination against tick-borne encephalitis following different primary vaccination schedules demonstrates at least 10 years antibody persistence.

Vaccine 2019 07 1;37(32):4623-4629. Epub 2018 Feb 1.

GSK, Via Fiorentina 1, 53100 Siena, Italy. Electronic address:

Background: Tick borne encephalitis (TBE) endemic zones are expanding. We previously evaluated long term persistence of antibody 5 years after the first booster immunization following different primary immunization schedules with the polygeline-free inactivated TBE vaccine (TBEvac) in adults and adolescents. Here, we report anti-TBE virus (TBEV) antibody persistence from 6 to 10 years post-booster administration.

Methods: This was a phase IV, open-label, single-center, second extension study (NCT01562444), conducted in Czechia. Healthy adults and adolescents ≥12 years who had received 3 different primary vaccination schedules (rapid, conventional and accelerated conventional) in the parent study and a booster dose before (12-18 months post-primary series completion) or at the beginning (3 years post-primary series completion) of the first extension study were screened and enrolled in this study. Blood samples were collected yearly and anti-TBEV antibody response was evaluated by neutralizing test (NT) antibody assays. Analysis was performed overall and per age strata: 15-49 years, ≥50 years, and ≥60 years.

Results: Of 206 screened individuals, 191 completed the study. Overall, 90-100% of participants in the all-screened set and ≥97% in the per-protocol set had the clinically meaningful threshold of protection (NT titers ≥10) across all timepoints, regardless of the primary vaccination schedule. Overall, antibody geometric mean titers (GMTs) varied from 134 to 343 in the all-screened set. Older age groups showed overall lower GMTs, although GMTs remained higher than NT titers ≥10 up to year 10 in all groups.

Conclusion: This study showed long-term persistence of anti-TBEV NT antibodies for up to 10 years after the first booster dose of TBEvac in all age groups, regardless of the primary vaccination schedule.
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http://dx.doi.org/10.1016/j.vaccine.2017.12.081DOI Listing
July 2019

A phase I, randomized, controlled, dose-ranging study of investigational acellular pertussis (aP) and reduced tetanus-diphtheria-acellular pertussis (TdaP) booster vaccines in adults.

Hum Vaccin Immunother 2018 01 27;14(1):45-58. Epub 2017 Nov 27.

b GSK, Vaccines , Siena , Italy.

Despite high vaccination coverage worldwide, pertussis has re-emerged in many countries. This randomized, controlled, observer-blind phase I study and extension study in Belgium (March 2012-June 2015) assessed safety and immunogenicity of investigational acellular pertussis vaccines containing genetically detoxified pertussis toxin (PT) (NCT01529645; NCT02382913). 420 healthy adults (average age: 26.8 ± 5.5 years, 60% female) were randomized to 1 of 10 vaccine groups: 3 investigational aP vaccines (containing pertussis antigens PT, filamentous hemagglutinin [FHA] and pertactin [PRN] at different dosages), 6 investigational TdaP (additionally containing tetanus toxoid [TT] and diphtheria toxoid [DT]), and 1 TdaP comparator containing chemically inactivated PT. Antibody responses were evaluated on days 1, 8, 30, 180, 365, and approximately 3 years post-booster vaccination. Cell-mediated immune responses and PT neutralization were evaluated in a subset of participants in pre-selected groups. Local and systemic adverse events (AEs), and unsolicited AEs were collected through day 7 and 30, respectively; serious AEs and AEs leading to study withdrawal were collected through day 365 post-vaccination. Antibody responses against pertussis antigens peaked at day 30 post-vaccination and then declined but remained above baseline level at approximately 3 years post-vaccination. Responses to FHA and PRN were correlated to antigen dose. Antibody responses specific to PT, toxin neutralization activity and persistence induced by investigational formulations were similar or significantly higher than the licensed vaccine, despite lower PT doses. Of 15 serious AEs, none were considered vaccination-related; 1 led to study withdrawal (premature labor, day 364; aP4 group). This study confirmed the potential benefits of genetically detoxified PT antigen. All investigational study formulations were well tolerated.
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http://dx.doi.org/10.1080/21645515.2017.1385686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791588PMC
January 2018

One-year immunogenicity kinetics and safety of a purified chick embryo cell rabies vaccine and an inactivated Vero cell-derived Japanese encephalitis vaccine administered concomitantly according to a new, 1-week, accelerated primary series.

J Travel Med 2016 Mar 19;23(3). Epub 2016 Mar 19.

Novartis Vaccines and Diagnostics, Srl (a GSK company), Siena, Italy.

Background: Conventional rabies pre-exposure prophylaxis (PrEP) and Japanese encephalitis (JE) primary series vaccination regimens each require up to 4 weeks to complete and, thus, may not be feasible for individuals who need these immunizations on short notice. This Phase 3b, randomized, controlled, observer-blind study evaluated the immunogenicity and safety of concomitant administration of a purified chick embryo cell culture rabies vaccine and an inactivated, adsorbed JE vaccine according to an accelerated (1 week) regimen when compared with the conventional regimens (4 weeks). This report describes the kinetics of immune responses up to 1 year after vaccination.

Methods: A total of 661 healthy adults (18 to ≤65 years) were randomized into the following accelerated or conventional vaccine regimens: Rabies + JE-Conventional, Rabies + JE-Accelerated, Rabies-Conventional and JE-Conventional. Immunogenicity was assessed by virus neutralization tests. Safety and tolerability were also evaluated.

Results: Irrespective of rabies vaccination regimen, ≥97% of subjects had adequate levels of rabies virus neutralizing antibody (RVNA) concentrations (≥0.5 IU/ml) up to Day 57, with percentages of subjects with RVNA concentrations ≥0.5 IU/ml at Day 366 ranging between 68% in the Rabies + JE-Accelerated group and 80% of subjects in the Rabies-Conventional group. The Rabies + JE-Accelerated group revealed high JE neutralizing antibody titers at all-time points. At Day 366, the percentage of subjects with antibody titers indicative of seroprotection (PRNT50 titers ≥1:10) remained high across JE vaccine groups (86-94%).

Conclusions: The accelerated PrEP rabies and JE vaccination regimens, once licensed, could represent a valid alternative in the short-term to currently recommended conventional regimens. The concomitant administration of these two vaccines does not compromise immune responses to any of the vaccine antigens particularly when aiming for short-term protection. Further evidence will clarify the need for and timing to administration of rabies vaccine booster doses in subjects primed with an accelerated PrEP regimen. (NCT01662440).
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http://dx.doi.org/10.1093/jtm/taw011DOI Listing
March 2016

Evaluation of rabies immunogenicity and tolerability following a purified chick embryo cell rabies vaccine administered concomitantly with a Japanese encephalitis vaccine.

Travel Med Infect Dis 2015 May-Jun;13(3):241-50. Epub 2015 May 18.

Novartis Vaccines and Diagnostics Srl - a GSK company, Siena, Italy. Electronic address:

Background: For individuals traveling at short notice to rabies and Japanese encephalitis (JE) endemic countries, concomitant administration of travel vaccines within a short period is often required.

Methods: The aim of this study was to determine whether an accelerated (one-week: Days 1-8) pre-exposure rabies (Rabipur(®), Novartis Vaccines) vaccination regimen administered concomitantly with a Japanese encephalitis (JE) vaccination (Ixiaro(®), Valneva) regimen, is non-inferior to the standard (four-week: Days 1, 8, 29) rabies regimen administered alone or concomitantly with the JE vaccine. Healthy adults (18 to ≤ 65 years) were randomized into Rabies + JE-Standard, Rabies + JE-Accelerated, Rabies-Standard and JE-Standard groups. Relative immunogenicity for rabies in each regimen was assessed using the rapid fluorescent focus inhibition test. Safety was evaluated up to and including Day 57.

Results: Non-inferior immunogenicity for rabies was established between the Rabies + JE-Accelerated group compared to both the Rabies-Standard and Rabies + JE-Standard groups; as well as between the Rabies + JE-Standard regimen and the Rabies-Standard regimen. By Day 57, adequate neutralizing levels were achieved by 97-100% of subjects across all groups. Adverse events (AEs) were comparable for all groups.

Conclusions: An accelerated pre-exposure rabies and JE vaccination regimen is non-inferior to the standard four-week rabies regimen and may thus provide a more convenient regimen for individuals traveling to endemic countries at short notice. NCT01662440.
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http://dx.doi.org/10.1016/j.tmaid.2015.05.008DOI Listing
March 2016

Immunogenicity and safety of cell-derived MF59®-adjuvanted A/H1N1 influenza vaccine for children.

Hum Vaccin Immunother 2015 ;11(2):358-76

a Clinic for Children and Youth; Dr. Horst Schmidt Clinics ; Wiesbaden , Germany.

Mass immunization of children has the potential to decrease infection rates and prevent the transmission of influenza. We evaluated the immunogenicity, safety, and tolerability of different formulations of cell-derived MF59-adjuvanted and nonadjuvanted A/H1N1 influenza vaccine in children and adolescents. This was a randomized, single-blind, multicenter study with a total of 666 healthy subjects aged 6 months-17 y in one of 3 vaccination groups, each receiving formulations containing different amounts of influenza A/H1N1 antigen with or without MF59. A booster trivalent seasonal MF59 vaccine was administered one year after primary vaccinations. Antibody titers were assessed by hemagglutination inhibition (HI) and microneutralization assays obtained on days 1, 22, 43, 366, and 387 (3 weeks post booster). Safety was monitored throughout the study. One vaccination with 3.75 μg of A/H1N1 antigen formulated with 50% MF59 (3.75_halfMF59) or 7.5 μg of A/H1N1 antigen formulated with 100% MF59 (7.5_fullMF59) induced an HI titer ≥1:40 in >70% of children in the 1-<3, 3-8, and 9-17 y cohorts; however, 2 vaccinations with nonadjuvanted 15 μg A/H1N1 antigen were needed to achieve this response in the 1-<3 and 3-8 y cohorts. Among children aged 6-11 months, 1 dose of 7.5_fullMF59 resulted in an HI titer ≥1:40 in >70% while 2 doses of 3.75_halfMF59 were required to achieve this result. All vaccines were well tolerated. Our findings support the immunogenicity and safety of the 3.75_halfMF59 (2 doses for children <12 months) and 7.5_fullMF59 vaccine formulations for use in children and adolescents aged 6 months to 17 y The use of the 3.75_halfMF59 could have the benefit of antigen and adjuvant sparing, increasing the available vaccine doses allowing vaccination of more people.
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http://dx.doi.org/10.4161/21645515.2014.987014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514327PMC
December 2015

mTOR inhibition improves immune function in the elderly.

Sci Transl Med 2014 Dec;6(268):268ra179

Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.

Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.
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http://dx.doi.org/10.1126/scitranslmed.3009892DOI Listing
December 2014

Safety and immunogenicity of an MF59-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age.

Vaccine 2015 Jan 11;33(1):174-81. Epub 2014 Nov 11.

Novartis Vaccines and Diagnostics S.r.l., Siena, Italy.

Objectives: This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects.

Methods: Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months).

Results: A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:40>70%; seroconversion>40%; and GMR>2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event.

Conclusions: An MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3-17 years old.
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http://dx.doi.org/10.1016/j.vaccine.2014.10.085DOI Listing
January 2015

A dose-ranging study of MF59(®)-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination.

Hum Vaccin Immunother 2014 ;10(8):2395-407

a Primary Physicians Research, Medicine; Pittsburgh, PA USA.

Background: During development of an A/H1N1 pandemic influenza vaccine, this study was performed to identify the antigen and adjuvant content which would provide optimal antibody response and persistence in adults and the elderly. Dose-sparing strategies, such as inclusion of adjuvants, are critical in ensuring the widest possible population coverage in the event of an influenza pandemic, despite a limited global capacity for vaccine manufacture.

Methods: Healthy subjects aged 18-64 years (n = 1240) and ≥65 years (n = 1352) were vaccinated with 1 of 8 investigational vaccine formulations varying in antigen quantity (3.75 µg to 30 µg of hemagglutinin) and MF59(®) adjuvant (none, half dose, or full dose). All subjects received 2 vaccine doses administered 3 weeks apart. Antibody response was assessed by hemagglutination inhibition assay 1 and 3 weeks after administration of first and second doses. Antibody persistence was assessed after 6 and 12 mo. Vaccine safety was monitored over 12 mo.

Results: All 8 investigational A/H1N1 vaccine formulations were well tolerated, and rapidly induced high antibody titers which met all of the Center for Biologics Evaluation and Research (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria 3 weeks after one dose. The highest antibody titers were observed in participants vaccinated with higher quantities of antigen and adjuvant.

Conclusion: A single vaccine dose containing 3.75 µg of A/California/7/2009 (H1N1) antigen with MF59 adjuvant was identified as optimal for young to middle-aged (18-64 years) and older (≥65 years) adult populations.
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http://dx.doi.org/10.4161/hv.29393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896790PMC
July 2015

Immunogenicity and tolerability of an MF59-adjuvanted, egg-derived, A/H1N1 pandemic influenza vaccine in children 6-35 months of age.

Pediatr Infect Dis J 2014 Dec;33(12):e320-9

From the *Zentrum für Kinder-und Jugendmedizin, Universitätsmedizin, Rheinland-Pfalz, Germany; †Center for Vaccinology, Ghent University and University Hospital, Ghent, Belgium; ‡Vaxinostics BV, University Vaccine Center Rotterdam Nijmegen, Rotterdam, The Netherlands; §Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile; ¶Hospital Maternidad Ntra Sra. de la Altagracia, Gazcue, Santo Domingo, The Dominican Republic; and ‖Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts.

Background: Vaccines against pandemic A/H1N1 influenza should provide protective immunity in children, because they are at greater risk of disease than adults. This study was conducted to identify the optimal dose of an MF59®-adjuvanted, egg-derived, A/H1N1 influenza vaccine for young children.

Methods: Children 6-11 months (N = 144) and 12-35 months (N = 186) of age received vaccine formulations containing either 3.75 μg antigen with half the standard dose of MF59 or 7.5 μg antigen with a standard dose of MF59, or a nonadjuvanted formulation containing 15 μg antigen (children 12-35 months only). Participants were given 2 primary vaccine doses 3 weeks apart, followed by 1 booster dose of MF59-adjuvanted seasonal influenza vaccine 1 year later. Immunogenicity was assessed by hemagglutination inhibition and microneutralization assays.

Results: All vaccine formulations were highly immunogenic and met all 3 European licensure criteria after 2 doses. MF59-adjuvanted vaccines met all licensure criteria after 1 dose in both age cohorts, while nonadjuvanted vaccine did not meet all criteria after 1 dose in children 12-35 months. A single booster dose was highly immunogenic, and stable antibody persistence was observed in response to all vaccines. All vaccines were well tolerated.

Conclusions: In this study, a single dose of 3.75 μg antigen with half the standard dose of MF59 was shown to be optimal, providing adequate levels of immediate and long-term antibodies in pediatric subjects 6-35 months of age. These data demonstrated that MF59 adjuvant allowed for reduced antigen content and promoted significant long-term antibody persistence in children, with a satisfactory safety profile.
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http://dx.doi.org/10.1097/INF.0000000000000462DOI Listing
December 2014

A phase III single arm, multicenter, open-label study to assess the immunogenicity and tolerability of a pentavalent DTwP-HepB-Hib vaccine in indian infants.

Hum Vaccin Immunother 2013 Sep 19;9(9):1903-9. Epub 2013 Jun 19.

Rajarajeshwari Medical College & Hospital; Bangalore, India.

Compliance with recommended vaccinations for Indian infants is facilitated by using combination vaccines to minimize the number of required injections. The ready-to-use, preservative free, fully-liquid combination DTwP-HepB-Hib vaccine, Quinvaxem(®), offers convenience of administering five important vaccine antigens to infants in a single injection. This phase III, single-arm, multicenter study was designed to assess immunogenicity and safety of three doses of Quinvaxem(®) to Indian infants administered at 6, 10, and 14 weeks of age. Blood samples were taken prior to the first dose and at one month post last vaccination. Infants were observed clinically for any reaction approximately 30 min following each vaccination, and parents completed subject diaries for solicited local, systemic and any adverse events (AEs) following over a 5 d period. DTwP-HepB-Hib vaccine elicited strong immune responses that exceeded seroprotection/seroconversion thresholds against all vaccine antigens. At one month after third vaccination, percentages of infants achieving predefined protective antibody levels were 99% diphtheria; 100% tetanus; 98% Hepatitis B; 100% Hib short-term (≥ 0.15 µg/mL); 95% Hib long-term (≥ 1.0 µg/mL) protection; and relevant immune response was 99% for pertussis. The vaccine was well tolerated, with no vaccine-related serious AEs. Only one case of high fever (≥ 40 °C) was reported. The most frequently reported reactions were mild to moderate tenderness and erythema. Frequencies of all AEs declined with subsequent vaccinations. This study demonstrated that this convenient, fully-liquid DTwP-HepB-Hib vaccine is highly immunogenic and has a acceptable safety profile for use in Indian infants. ClinicalTrials.gov Identifier: NCT01470287. Clinical Trials Registry of India Number: CTRI/2011/11/002118.
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http://dx.doi.org/10.4161/hv.25166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906354PMC
September 2013

A randomised, single-blind, dose-range study to assess the immunogenicity and safety of a cell-culture-derived A/H1N1 influenza vaccine in adult and elderly populations.

Vaccine 2012 Jul 22;30(32):4820-7. Epub 2012 May 22.

Division of Communicable Diseases, Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland.

Background: Modern cell-culture production techniques and the use of adjuvants helps to ensure that the global demand for pandemic influenza vaccine can be met. This study aimed to assess the immunogenicty and safety profiles of various cell-culture-derived A/H1N1 pandemic vaccine formulations in healthy adult and elderly subjects.

Methods: Adult (18-60 years) subjects (n=544) received vaccine either containing 3.75 μg of antigen with half the standard dose of MF59 (Novartis Vaccines and Diagnostics) adjuvant, 7.5 μg antigen with a full dose of MF59, or a non-adjuvanted vaccine containing 15 μg of antigen. Elderly (≥ 61 years) subjects (n=268) received either the 3.75 μg or 7.5 μg adjuvanted formulations. Two priming vaccine doses were administered 3 weeks apart, followed by a single booster dose of seasonal influenza vaccine 1 year later. Immunogenicity was assessed 3 weeks after each vaccination. The safety profile of each formulation was evaluated throughout the study.

Results: A single primary dose of each A/H1N1 vaccine formulation was sufficient to meet all three European (CHMP) licensure criteria for pandemic influenza vaccines in adult subjects. Two licensure criteria were met after one vaccine dose in elderly subjects; two primary doses were required to meet all three criteria in this age group. The highest antibody titres were observed in response to the 7.5 μg vaccine containing a full dose of MF59 adjuvant. All subjects rapidly generated seroprotective antibody titres in response to booster vaccination.

Conclusion: This study identified one 3.75 μg vaccine dose containing half the standard dose of MF59 adjuvant as optimal for adults, two doses were optimal for elderly subjects. The antigen-sparing properties of MF59, and rapid, modern, cell-culture production techniques represent significant steps towards meeting the global demand for influenza vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2012.05.013DOI Listing
July 2012

One dose of an MF59-adjuvanted pandemic A/H1N1 vaccine recruits pre-existing immune memory and induces the rapid rise of neutralizing antibodies.

Vaccine 2012 Jun 19;30(27):4086-94. Epub 2012 Apr 19.

Research Development, Novartis Vaccines and Diagnostics srl, Siena, Italy.

Protective antibody responses to a single dose of 2009 pandemic vaccines have been observed in the majority of healthy subjects aged more than 3 years. These findings suggest that immune memory lymphocytes primed by previous exposure to seasonal influenza antigens are recruited in the response to A/H1N1 pandemic vaccines and allow rapid seroconversion. However, a clear dissection of the immune memory components favoring a fast response to pandemic vaccination is still lacking. Here we report the results from a clinical study where antibody, CD4+ T cell, plasmablast and memory B cell responses to one dose of an MF59-adjuvanted A/H1N1 pandemic vaccine were analyzed in healthy adults. While confirming the rapid appearance of antibodies neutralizing the A/H1N1 pandemic virus, we show here that the response is dominated by IgG-switched antibodies already in the first week after vaccination. In addition, we found that vaccination induces the rapid expansion of pre-existing CD4+ T cells and IgG-memory B lymphocytes cross-reactive to seasonal and pandemic A/H1N1 antigens. These data shed light on the different components of the immune response to the 2009 H1N1 pandemic influenza vaccination and may have implications in the design of vaccination strategies against future influenza pandemics.
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http://dx.doi.org/10.1016/j.vaccine.2012.04.020DOI Listing
June 2012

Assessment of the immunogenicity and safety of varying doses of an MF59®-adjuvanted cell culture-derived A/H1N1 pandemic influenza vaccine in Japanese paediatric, adult and elderly subjects.

Vaccine 2012 Jul 1;30(33):5030-7. Epub 2012 Apr 1.

CPC Clinic, Medipolis Medical Research Institute, Kagoshima, Japan.

Introduction: Effective vaccination strategies are required to combat future influenza pandemics. Here we report the results of three independent clinical trials performed in Japan to assess the immunogenicity, tolerability and safety of varying doses of a cell culture-derived MF59(®)-adjuvanted A/H1N1 pandemic vaccine in healthy Japanese paediatric, adult and elderly subjects.

Methods: One hundred and twenty-three children (6 months-18 years), and 200 adults (19-60 years) were randomly assigned in a 1:1 ratio to receive two doses of vaccine containing either 7.5 μg antigen with a full (9.75 mg) adjuvant dose, or 3.75 μg antigen with a half (4.875 mg) adjuvant dose. One hundred elderly (≥ 61 years) subjects received only the low antigen/adjuvant vaccine formulation. Immunogenicity was assessed by haemagglutination inhibition assay at baseline and three weeks after the first and second vaccine doses on Days 22 and 43, respectively. Solicited and unsolicited adverse reactions were recorded for seven and 21 days post-immunization, respectively.

Results: In adult and elderly subjects, a single low antigen/adjuvant dose vaccination was sufficient to meet all of the three European licensure criteria established for influenza vaccines. One high, or two low antigen/adjuvant dose vaccinations were required to meet the licensure criteria in paediatric subjects. Both vaccine formulations were well tolerated, with the majority of adverse reactions mild to moderate in severity. None of the five serious adverse events reported throughout the three trials were considered to be vaccine-related by the investigators.

Conclusion: The use of MF59 adjuvant allows for much reduced vaccine antigen content, and a single dose administration schedule in adults and the elderly. The production of pandemic vaccine using modern cell culture techniques is highly advantageous in terms of the quantity, quality, and rapidity of antigen production; these benefits, in combination with the use of MF59, maximize manufacturing capacity and global vaccine supply. These data support the suitability of the investigational vaccine for use in the Japanese paediatric, adult, and elderly populations.
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http://dx.doi.org/10.1016/j.vaccine.2012.03.053DOI Listing
July 2012

A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects.

Vaccine 2012 May 22;30(23):3470-7. Epub 2012 Mar 22.

Division of Communicable Diseases, Institute for Social and Preventive Medicine, University of Zurich, 8001 Zurich, Switzerland.

Background: Vaccines against pandemic A/H1N1 influenza are required to protect the entire population. This dose range study aimed to identify priming antigen and adjuvant doses resulting in optimal levels of antibody-mediated protection after primary and one-year booster immunizations.

Methods: This randomised trial enrolled 410 healthy adult (18-60 years) and 251 healthy elderly (>60 years) participants. Subjects received vaccine containing either 3.75 μg or 7.5 μg antigen, adjuvanted with half the standard dose, or a standard dose of MF59(®) (Novartis Vaccines) adjuvant, respectively. An additional adult cohort received non-adjuvanted vaccine containing 15 μg antigen. Two doses of investigational vaccine were administered three weeks apart, followed by a single booster dose of adjuvanted seasonal influenza vaccine one year after priming. Immunogenicity was assessed by haemagglutination inhibition and microneutralization assays pre- and post-immunization, the safety profile of each vaccine was also evaluated.

Results: All of the vaccine formulations investigated were highly immunogenic and well tolerated in both adult and elderly subjects. The 7.5 μg formulation induced the highest antibody titres after primary and booster immunizations, and resulted in better long-term antibody persistence, in both age groups. Assessment according to European licensure criteria for influenza vaccines concluded that single adjuvanted priming doses containing 3.75 μg and 7.5 μg antigen were optimal for the adult and elderly populations, respectively.

Conclusions: These data demonstrate that one priming dose of MF59-adjuvanted A/H1N1 vaccine provided healthy adult (3.75 μg or 7.5 μg formulations) and healthy elderly (7.5 μg formulation) individuals with adequate levels of seroprotection. Booster administration after two priming doses of either vaccine formulation resulted in the rapid development of seroprotective antibody titres.

Trial Registration: www.clinicaltrials.gov (NCT00971906).
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http://dx.doi.org/10.1016/j.vaccine.2012.03.017DOI Listing
May 2012

Safety assessment and immunogenicity of a cell-culture-derived influenza vaccine in adults and elderly subjects over three successive influenza seasons.

Hum Vaccin Immunother 2012 May 1;8(5):645-52. Epub 2012 May 1.

Early Development Services CEE, PRA International, Warszawa, Poland.

Background: Adult and elderly subjects previously immunized with cell culture-derived (CCIV; Optaflu(®)) or egg-derived (TIV; Agrippal(®)) trivalent influenza vaccines were enrolled in two extension studies (E1 and E2) to evaluate safety and immunogenicity after revaccination with CCIV/TIV alone or in combination with concomitant pneumococcal vaccine (PV).

Methods: Adults and elderly subjects (n = 2609) were randomized 1:1 in E1 and allocated 3:1 in E2 to receive CCIV/TIV. In E2, a subset of elderly subjects was randomized to receive CCIV/TIV, with or without PV. Adverse reactions were monitored for six months and immunogenicity was assessed by hemagglutination inhibition (HI) assay using CHMP criteria.

Results: Overall, the safety profile of both vaccines was similar, no serious adverse events related to either vaccine occurred. Mild or moderate pain was the most commonly reported reaction. Reactogenicity was slightly higher in elderly subjects receiving CCIV/TIV concomitantly with PV [46% vs. 37%; p = non-significant (NS)]. Both vaccines met CHMP licensure criteria for adults and elderly subjects. With concomitant CCIV and PV, all three CHMP criteria were met for A/H1N1 and A/H3N2, whereas the B strain only met seroprotection and GMR criteria.

Conclusions: Safety and immunogenicity of CCIV was not influenced by the type of vaccine received previously or by concomitant PV administration.
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http://dx.doi.org/10.4161/hv.19493DOI Listing
May 2012

Immunogenicity, safety and reactogenicity of a mammalian cell-culture-derived influenza vaccine in healthy children and adolescents three to seventeen years of age.

Pediatr Infect Dis J 2012 May;31(5):494-500

University of Tampere Medical School, Tampere, Finland. .

Background: The safety and immunogenicity of the cell-culture-derived seasonal trivalent influenza vaccine ([CCIV]; Optaflu) has been reported previously in adults and the elderly. In this study, we compared the safety, reactogenicity and immunogenicity of CCIV with a conventional egg-derived trivalent influenza vaccine (TIV) in a healthy pediatric population.

Methods: A total of 3604 subjects were randomized to receive 2 doses of CCIV or TIV (3-8 years, n = 2630) at a 28-day interval or a single vaccination (9-17 years, n = 974). Antibody levels on days 1, 29 and 50 were measured by hemaglutination inhibition assay using egg-derived and cell-derived test antigens. Adverse reactions were solicited via memory aids for 7 days after each injection, and unsolicited adverse events/serious adverse events were collected for 6 months postvaccination.

Results: Noninferiority of CCIV versus TIV was demonstrated for most immunogenicity measures, particularly by using cell-derived antigen in the hemaglutination inhibition assay. In 3- to 8-year-olds (the primary objective), both CCIV and TIV met all 3 Committee for Medicinal Products for Human Use immunogenicity criteria for A/H1N1 and A/H3N2 strains. Lower immune responses were observed against the B strain, fulfilling Committee for Medicinal Products for Human Use criteria only for geometric mean ratio (TIV, CCIV) and seroconversion rate (TIV, CCIV [cell-derived antigen]). Both CCIV and TIV were safe and well tolerated, with no differences in local and systemic solicited reactions or in unsolicited adverse events/serious adverse events.

Conclusion: CCIV produced in mammalian cell culture is a safe, well-tolerated and immunogenic alternative to conventional egg-derived influenza vaccines for children and adolescents.
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http://dx.doi.org/10.1097/INF.0b013e31824bb179DOI Listing
May 2012

MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines.

Sci Transl Med 2011 Jun;3(85):85ra48

Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.

Oil-in-water adjuvants have been shown to improve immune responses against pandemic influenza vaccines as well as reduce the effective vaccine dose, increasing the number of doses available to meet global vaccine demand. Here, we use genome fragment phage display libraries and surface plasmon resonance to elucidate the effects of MF59 on the quantity, diversity, specificity, and affinity maturation of human antibody responses to the swine-origin H1N1 vaccine in different age groups. In adults and children, MF59 selectively enhanced antibody responses to the hemagglutinin 1 (HA1) globular head relative to the more conserved HA2 domain in terms of increased antibody titers as well as a more diverse antibody epitope repertoire. Antibody affinity, as inferred by greatly diminished (≥10-fold) off-rate constants, was significantly increased in toddlers and children who received the MF59-adjuvanted vaccine. Moreover, MF59 also improved antibody affinity maturation after each sequential vaccination against avian H5N1 in adults. For both pandemic influenza vaccines, there was a close correlation between serum antibody affinity and virus-neutralizing capacity. Thus, MF59 quantitatively and qualitatively enhances functional antibody responses to HA-based vaccines by improving both epitope breadth and binding affinity, demonstrating the added value of such adjuvants for influenza vaccines.
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http://dx.doi.org/10.1126/scitranslmed.3002336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501657PMC
June 2011

Clinical efficacy of cell culture–derived and egg‐derived inactivated subunit influenza vaccines in healthy adults.

Clin Infect Dis 2010 Nov;51(9):997-1004

Saint Louis University Medical School, St. Louis, Missouri, USA.

Background: More efficient methods are needed to manufacture influenza vaccines. This trial compared the efficacy of cell culture-derived influenza vaccine (CCIV) and egg-derived trivalent inactivated vaccine (TIV) with placebo against laboratory-confirmed influenza illness in healthy adults in the United States, Finland, and Poland during the 2007-2008 influenza season.

Methods: A total of 11,404 study participants aged 18-49 years were randomized equally to receive CCIV (Optaflu; n = 3828), TIV (Agrippal; n = 3676), or placebo (n = 3900). Each participant was observed during a 6-month study surveillance period. Nasal and throat swabs for virus isolation and characterization were collected from all patients with influenza-like illness. Vaccine immunogenicity was evaluated in a subset of 1045 participants.

Results: Efficacy of CCIV and TIV against vaccine-like (83.8% [1-sided 97.5% confidence interval [CI] lower limit, 61.0%] and 78.4% [1-sided 97.5% CI lower limit, 52.1%], respectively) and all circulating influenza virus strains (69.5% [1-sided 97.5% CI lower limit, 55.0%] and 63.0% [1-sided 97.5% lower limit, 46.7%], respectively) exceeded the Center for Biologics Evaluation and Research efficacy criteria. Immunogenicity of both vaccines exceeded the Center for Biologics Evaluation and Research licensing criteria. Both vaccines were well tolerated, with similar safety profiles. Most solicited reactions were mild to moderate in severity and transient. No vaccination-related serious adverse events were reported; no withdrawals resulted from vaccine-related adverse events.

Conclusions: Both CCIV and TIV were effective in preventing influenza caused by vaccine-like and by all circulating influenza virus strains, were well tolerated, and had good safety profiles. Both vaccines can be considered for annual influenza vaccination campaigns.

Clinical Trials Registration: NCT00630331.
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http://dx.doi.org/10.1086/656578DOI Listing
November 2010

Comparison of half and full doses of an MF59-adjuvanted cell culture-derived A/H1N1v vaccine in Japanese children.

Adv Ther 2010 Jul 25;27(7):444-57. Epub 2010 Jun 25.

Yasuda Clinic, Minami-ku, Kyoto, Japan.

Introduction: The substantial pandemic (A/H1N1v) influenza disease burden in children highlights the need for effective vaccination. We report the results of modern cell culture technology, lower doses of antigen, and different doses of MF59(R) adjuvant (Novartis Vaccines, Marburg, Germany), on the immunogenicity and safety profile in a healthy Japanese pediatric population.

Methods: A total of 123 children from 6 months to 19 years of age were randomly assigned in a 1:1 ratio to receive, at 21-day intervals, two doses of either 3.75 microg antigen with 50% of the standard MF59 dose (group A) or 7.5 microg antigen and 100% standard MF59 dose (group B). Antibody levels were measured by hemagglutinin inhibition (HI) and microneutralization assays on day 1 and on days 22 and 43 (3 weeks after the first and second vaccinations, respectively). Solicited adverse events were reported for 7 days after each injection and spontaneous events were reported throughout the study period.

Results: At 3 weeks after the first vaccination, seroprotective HI antibodies (titers >or=40) were observed in 56% and 78% of subjects from groups A and B, respectively; 100% in both groups exhibited HI titers >or=40 after the second dose. The reactogenicity profile was acceptable, with local and systemic reactions described as mainly mild to moderate in severity. Five serious adverse events were reported, but none related to the study vaccine.

Conclusion: One dose of cell culture-derived A/H1N1v vaccine containing 7.5 microg antigen with the full MF59 adjuvant dose was immunogenic and well tolerated in healthy Japanese children, meeting all three European Union Committee for Medicinal Products for Human Use (EU CHMP) licensure criteria. Two doses of 3.75 microg antigen with 50% of the standard MF59 dose fulfilled these licensure criteria.
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http://dx.doi.org/10.1007/s12325-010-0043-4DOI Listing
July 2010

Dose ranging of adjuvant and antigen in a cell culture H5N1 influenza vaccine: safety and immunogenicity of a phase 1/2 clinical trial.

Vaccine 2010 Jan 14;28(3):840-8. Epub 2009 Oct 14.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.

Background: Dose-sparing strategies and new production technologies will be necessary to produce adequate supplies of vaccines for pandemic influenza. One approach is to include adjuvant, which can reduce the amount of antigen required for immunization and stimulate cross-reactive responses to drifted variants of novel viruses. Dose-sparing studies of adjuvant, itself a finite resource, have not previously been reported for H5N1 vaccine development.

Methodology/principal Findings: A total of 753 healthy 18-40-year-old adults were randomized to one of 12 groups (N approximately 60/group) to receive two intramuscular doses, 21 days apart, of 3.75, 7.5 or 15 microg of cell culture grown influenza A/H5N1 hemagglutinin (A/Indonesia/5/2005 (H5N1)/PR-8-IBCDC-RG2), each dose level formulated with 0%, 25%, 50% or 100% of the MF59 dose contained in licensed influenza vaccine. 752 subjects actually received one dose, and 695 a second dose. Serum hemagglutination inhibition and neutralizing antibody levels, were determined before and 21 days after each dose. Safety and reactogenicity were assessed by self-completed diary cards. Nonadjuvanted H5N1 formulations were poorly immunogenic, but antibody responses were significantly enhanced by all doses of MF59 for each antigen level. The 3.75 microg H5N1 containing 50% MF59 satisfied the European criteria for pandemic vaccine licensure. All formulations were well tolerated, although MF59 dose-dependent increases in the frequency of injection site pain were observed. The frequencies of injection site and systemic reactions were lower after receipt of the second dose of vaccine. No vaccine-related SAE was reported.

Conclusions: Dose-sparing of both antigen and adjuvant is possible without compromising immunogenicity, while improving reactogenicity and is a promising strategy that will expand the availability of vaccines for global control of pandemic influenza.
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http://dx.doi.org/10.1016/j.vaccine.2009.10.019DOI Listing
January 2010

Safety and immunogenicity of a novel influenza subunit vaccine produced in mammalian cell culture.

J Infect Dis 2009 Sep;200(6):841-8

Center for Clinical Pharmacology Research, Monipol, Krakow, Poland.

Background: Immunization remains the best prevention strategy for influenza, but production constraints for egg-based influenza vaccines have prompted the development of innovative cell culture manufacturing processes. Here, we describe a novel cell culture-derived influenza vaccine (CCIV) produced in Madin-Darby canine kidney cells.

Methods: This phase 3, observer-blind, randomized, multicenter study in Poland compared the immunogenicity of a CCIV and a conventional egg-based vaccine. Participants, stratified by age (adults 18-60 years, n = 1300; elderly persons > or = 61 years, n = 1354), received a single intramuscular vaccination. Immunogenicity was assessed 21 days later by hemagglutination inhibition assay. Reactogenicity was assessed using self-completed diary cards.

Results: The immunogenicity of CCIV was noninferior to that of the conventional vaccine for all 3 vaccine strains in both age groups, regardless of underlying health status. Both vaccines fulfilled European Union registration criteria and were well tolerated, with similar incidences of solicited local and systemic reactions in both age groups; the only significant difference was an increased frequency of mild or moderate pain with CCIV than the conventional vaccine among adult (22% vs 17%; P < .05) and elderly (9% vs 5%; P < .001) vaccinees.

Conclusions: CCIV was well tolerated and highly immunogenic in adults 18 years of age or older. Cell culture may offer greater flexibility of supply during periods of high demand for both seasonal and pandemic vaccines.
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http://dx.doi.org/10.1086/605505DOI Listing
September 2009

A novel mammalian cell-culture technique for consistent production of a well-tolerated and immunogenic trivalent subunit influenza vaccine.

Vaccine 2009 Oct 8;27(43):6022-9. Epub 2009 Aug 8.

Vilnius University, Vilnius, Lithuania.

Conventional influenza vaccine production methods have limitations due to their reliance on chicken eggs. We evaluated whether a mammalian cell-culture system could reliably produce an influenza vaccine with favourable tolerability and immunogenicity profiles. Adult subjects (n=1200; 18-60 years of age) were randomized (2:2:2:1) to receive either one of three lots of a cell-culture-derived influenza vaccine (CCIV) or an egg-based trivalent inactivated influenza vaccine (TIV). Safety and reactogenicity were assessed using solicited indicators for 7 days post-vaccination, all other adverse events (AEs) were recorded for 21 days post-vaccination, and all serious AEs and AEs necessitating a physician's visit, and/or resulting in subject's withdrawal from the study, were collected for up to 6 months post-vaccination. Antibody titres were measured by haemagglutination inhibition (HI) assay using egg-based viral antigens. All three lots of CCIV had similar safety and tolerability profiles, analogous to those of the TIV. Lot-to-lot consistency was statistically demonstrated through bioequivalence for immunogenicity. Antibody titres assessed at 6 months demonstrated good persistence. This Phase III trial is the first to demonstrate lot-to-lot bioequivalence of a CCIV and persistence of immunogenicity in comparison with a TIV.
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http://dx.doi.org/10.1016/j.vaccine.2009.07.083DOI Listing
October 2009

Long-term solutions for the problem of vaccine shortages.

Expert Opin Biol Ther 2004 Jun;4(6):989-92

Chiron Vaccines, Via Fiorentina 1, 53100 Siena, Italy.

During the past few years, vaccine shortage has been a serious problem affecting both developed and developing countries. The explanation is linked to the poor economic value associated with vaccines. Although every year the routine use of vaccines saves millions of lives, the economic value associated with them is negligible, especially if compared with the pharmaceutical market. This situation disincentives private investment, which prefers to focus on more profitable business. To overcome these problems, it is essential to recognise that the intangible value of vaccination (the value of being alive and healthy) represents the real value provided by vaccines. If the intangible value were to be included in the vaccine price, vaccines would become as attractive as other pharmaceuticals. While waiting for a long-term sustainable solution, public-private partnerships represent a way to increase vaccine value awareness and to decrease the risk for vaccine manufacturers. This article will provide examples of how public-private partnerships both in developed and developing countries have been established to handle specific problems concerning vaccination.
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http://dx.doi.org/10.1517/14712598.4.6.989DOI Listing
June 2004

The value of vaccines.

Vaccine 2003 Jun;21 Suppl 2:S110-3

IRIS, Chiron S.r.l., Via Fiorentina 1, I-53100 Siena, Italy.

Today, we have the technology to make vaccines against most infectious diseases and in theory we could free mankind from most of them. In spite of the great progress of science and technology, vaccines are an endangered species and there are increasing non-technological barriers to their development. Indeed, we have no mechanisms for developing vaccines needed only in developing countries, and in developed countries they are not a priority. Industry is walking away from vaccines and even the existing ones are in jeopardy. The reasons for the low interest in vaccines lie in the high risk and low profitability of the vaccine business. A story about the consequences that an infectious disease had on the economic development of the city of Siena in 1348 is used to show that our society is not calculating the intangible values deriving from vaccination. The failure of assigning the right value to vaccines and preventive medicine is a major risk of today's world that, having the opportunity of improving the proportion of healthy population, may have made the choice of increasing the number of chronically sick people.
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http://dx.doi.org/10.1016/s0264-410x(03)00209-3DOI Listing
June 2003

Meningitis C vaccine (North American vaccine).

Curr Opin Investig Drugs 2002 Jan;3(1):51-3

Chiron SpA, Siena, Italy.

North American Vaccine Inc (NAVI) has launched a conjugate polysaccharide vaccinefor the prevention of meningitis caused by group C meningococcal bacteria [433475]. The vaccine is based upon conjugate technology, incorporating the serogroup C polysaccharide (CPS) of all three major serogroups. Antibody-dependent, complement-mediated activity was demonstrated in mice and non-human primates, with no detectable adverse effects [277193]. Approval was filed for in the UK in January 2000 [353305]. In July 2000, Baxter received approval for NeisVac-C in the UK, and by September 2000 the vaccine was expected to be incorporated into the NHS's immunization campaign against meningitis C [381225]. NeisVac-C will initially appear labeled from NAVI; Baxter completed its acquisition of NAVI in June 2000 [375389]. Baxter estimates the worldwide global market for the vaccine at US $600 million per year [376204].
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January 2002

Resistance determinants and clonal diversity in group A streptococci collected during a period of increasing macrolide resistance.

Antimicrob Agents Chemother 2002 Jun;46(6):1816-22

Clinica delle Malattie Infettive, Sezione di Microbiologia, Dipartimento di Biologia Molecolare, Università degli Studi di Siena, I-53100 Siena, Italy.

Susceptibility to macrolides and lincosamides was investigated with 299 consecutive nonduplicate Streptococcus pyogenes clinical isolates collected over a 6-year period (1992 to 1997) from an area of central Italy. During this period, macrolide resistance rates steadily increased (from 9% in 1992 to 53% in 1997; P < 0.001). The increase was caused by isolates with a macrolide-lincosamide-streptogramin B resistance phenotype, carrying mostly erm(B) but also erm(TR) genes, that were not detected in the first 2 years and were detected with increasing prevalence (8, 5, 26, and 37%, respectively) during the following 4 years. During the same period, the prevalence of isolates with a macrolide resistance phenotype, carrying mef(A) determinants, did not vary significantly; on average it was 13%, with modest rate fluctuations in different years and no definite trend. Molecular typing revealed a remarkable clonal diversity among susceptible and resistant isolates and a notable heterogeneity of the genetic environment of the resistance genes. The analysis of clonal diversity in relation with resistance phenotypes and genotypes revealed that increased macrolide resistance rates were due to a complex interplay of different mechanisms, with a relevant contribution played by an "epidemic" spread of genetic elements carrying the erm(B) gene among the circulating streptococcal population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC127250PMC
http://dx.doi.org/10.1128/aac.46.6.1816-1822.2002DOI Listing
June 2002