Publications by authors named "Audino Podda"

31 Publications

Booster Vaccination With GVGH 1790GAHB GMMA Vaccine Compared to Single Vaccination in Unvaccinated Healthy European Adults: Results From a Phase 1 Clinical Trial.

Front Immunol 2019 8;10:335. Epub 2019 Mar 8.

GSK Vaccines Institute for Global Health, Siena, Italy.

The investigational vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti- lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2-3 years earlier (boosted group), compared to one dose in 28 vaccine-naïve individuals (vaccine-naïve group). Anti- LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day [D]1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naïve group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naïve groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naïve group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naïve participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naïve individuals. Vaccination was well tolerated.
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http://dx.doi.org/10.3389/fimmu.2019.00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418009PMC
September 2020

Education in Vaccinology: An Important Tool for Strengthening Global Health.

Front Immunol 2018 24;9:1134. Epub 2018 May 24.

GSK Vaccines Institute for Global Health, Siena, Italy.

Over the past 20 years, education of scientists and public health professionals in Vaccinology has increased dramatically. There are now many international, regional, and national courses that provide education in vaccinology. The proliferation of these courses and the high number of applications submitted demonstrate the increasing and continuous need for improved education in this field since, generally, comprehensive vaccinology training is not offered to medical and/or biological sciences students as part of their Universities courses and consequently there is insufficient knowledge of vaccine topics among health-care providers. Multidisciplinary vaccinology courses have not only educational purposes but they may also contribute to strengthening the development, testing, and use of vaccines, which remain the most efficient tool for infectious disease prevention. The courses available have a varied focus and prioritize topics based on the trainees' different levels of professional exposure and requirements. Overall, they might be classified in two key categories: (i) courses targeting students who, after their university studies in Medicine, Biology, etc., develop a strong interest in vaccines, would like to learn more about the various aspects of vaccinology, and potentially develop a career in this field (postgraduate courses); (ii) courses targeting postdoctoral professionals, who already have a sufficiently broad knowledge of vaccinology, but would like to develop stronger skills to be able to play a leading role in decision-making for vaccine development (advanced professional courses). Both postgraduate and professional courses are available and are based on comprehensive curricula. In the future, particular attention should be paid to include in the training curricula topics that might help vaccine development, efficient and sustainable vaccine introduction through epidemiologically sound vaccination programs, and best practices to address associated challenges, including vaccine hesitancy which could become a threat to successful implementation of vaccination programs, particularly in developed countries. In addition, it appears that the next phase of vaccinology training could benefit from a global and more structured platform that could facilitate exchanges and collaboration and amplify the current capacity for disseminating vaccine education for future vaccinology leaders around the world. This would be favored by synergizing the efforts currently devoted to vaccinology education. To initiate this process of analysis and systematization, a multinational effort is needed.
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http://dx.doi.org/10.3389/fimmu.2018.01134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976744PMC
July 2019

A Phase 2a Randomized Study to Evaluate the Safety and Immunogenicity of the 1790GAHB Generalized Modules for Membrane Antigen Vaccine against Administered Intramuscularly to Adults from a Shigellosis-Endemic Country.

Front Immunol 2017 22;8:1884. Epub 2017 Dec 22.

GSK Vaccines Institute for Global Health, Siena, Italy.

Shigellosis is a mild-to-severe diarrheal infection, caused by the genus , and is responsible for significant morbidity and mortality worldwide. We evaluated the safety and immunogenicity of an investigational vaccine (1790GAHB) based on generalized modules for membrane antigens (GMMA) in Kenya, a -endemic country. This phase 2a, observer-blind, controlled randomized study (NCT02676895) enrolled 74 healthy adults aged 18-45 years, of whom 72 were vaccinated. Participants received, in a 1:1:1 ratio, two vaccinations with the 1790GAHB vaccine at doses of either 1.5/25 μg of O antigen (OAg)/protein (group 1.5/25 μg) or 5.9/100 μg (group 5.9/100 μg) at day (D) 1 and D29, or vaccination with a quadrivalent meningococcal vaccine at D1 and tetanus, diphtheria, and acellular pertussis vaccine at D29 (control group). Solicited and unsolicited adverse events (AEs), serious AEs (SAEs), and AEs of special interest (neutropenia and reactive arthritis) were collected. Anti- lipopolysaccharide (LPS) serum immunoglobulin G (IgG) geometric mean concentrations (GMC) were evaluated at D1, D29, and D57 and compared to anti- LPS antibody levels in convalescent patients naturally exposed to . The percentages of participants with seroresponse were also calculated. The most frequently reported solicited local and systemic AEs across all groups were pain and headache, respectively. Only one case of severe systemic reaction was reported (severe headache after first vaccination in group 5.9/100 μg). Seven and three episodes of neutropenia, assessed as probably or possibly related to vaccination respectively, were reported in the investigational and control groups, respectively. No other SAEs were reported. Despite very high baseline anti- LPS serum IgG levels, the 1790GAHB vaccine induced robust antibody responses. At D29, GMC increased 2.10- and 4.43-fold from baseline in groups 1.5/25 and 5.9/100 μg, respectively, whereas no increase was observed in the control group. Antibody titers at D57 were not statistically different from those at D29. Seroresponse was 68% at D29 and 90% at D57 in group 1.5/25 μg, and 96% after each vaccination in group 5.9/100 μg. The 1790GAHB vaccine was well tolerated and highly immunogenic in a population of African adults, regardless of the GMMA OAg/protein content used.
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http://dx.doi.org/10.3389/fimmu.2017.01884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763125PMC
December 2017

Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe.

EBioMedicine 2017 Aug 15;22:164-172. Epub 2017 Jul 15.

GSK Vaccines Institute for Global Health, Siena, Italy. Electronic address:

Background: Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults.

Methods: To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France ("study 1") and the United Kingdom ("study 2") between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18-45years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100μg of OAg/μg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10μg ID, 0.29/5, 1.2/20, 4.8/80μg IN and 0.29/5μg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei.

Findings: Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses ≥1.5/25μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody.

Interpretation: Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100μg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines.
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http://dx.doi.org/10.1016/j.ebiom.2017.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552227PMC
August 2017

Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model.

Clin Infect Dis 2017 04;64(8):1066-1073

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.

Background: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection.

Methods: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge.

Results: The primary study objective was achieved following challenge with 1-5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24-85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia.

Conclusions: Challenge with S. Paratyphi A at a dose of 1-5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology.

Clinical Trials Registration: NCT02100397.
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http://dx.doi.org/10.1093/cid/cix042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439345PMC
April 2017

Neutropenia as an Adverse Event following Vaccination: Results from Randomized Clinical Trials in Healthy Adults and Systematic Review.

PLoS One 2016 4;11(8):e0157385. Epub 2016 Aug 4.

Novartis Vaccines Institute for Global Health, Siena, Italy.

Background: In the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance.

Methodology: We report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context.

Principal Findings: Both in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations.

Conclusions: It is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events.

Trial Registration: ClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157385PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974007PMC
August 2017

The transfer and decay of maternal antibody against Shigella sonnei in a longitudinal cohort of Vietnamese infants.

Vaccine 2016 Feb 29;34(6):783-90. Epub 2015 Dec 29.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

Background: Shigella sonnei is an emergent and major diarrheal pathogen for which there is currently no vaccine. We aimed to quantify duration of maternal antibody against S. sonnei and investigate transplacental IgG transfer in a birth cohort in southern Vietnam.

Methods And Results: Over 500-paired maternal/infant plasma samples were evaluated for presence of anti-S. sonnei-O IgG and IgM. Longitudinal plasma samples allowed for the estimation of the median half-life of maternal anti-S. sonnei-O IgG, which was 43 days (95% confidence interval: 41-45 days). Additionally, half of infants lacked a detectable titer by 19 weeks of age. Lower cord titers were associated with greater increases in S. sonnei IgG over the first year of life, and the incidence of S. sonnei seroconversion was estimated to be 4/100 infant years. Maternal IgG titer, the ratio of antibody transfer, the season of birth and gestational age were significantly associated with cord titer.

Conclusions: Maternal anti-S. sonnei-O IgG is efficiently transferred across the placenta and anti-S. sonnei-O maternal IgG declines rapidly after birth and is undetectable after 5 months in the majority of children. Preterm neonates and children born to mothers with low IgG titers have lower cord titers and therefore may be at greater risk of seroconversion in infancy.
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http://dx.doi.org/10.1016/j.vaccine.2015.12.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742520PMC
February 2016

Immunogenicity and safety of the Vi-CRM197 conjugate vaccine against typhoid fever in adults, children, and infants in south and southeast Asia: results from two randomised, observer-blind, age de-escalation, phase 2 trials.

Lancet Infect Dis 2014 Feb 28;14(2):119-29. Epub 2013 Nov 28.

Novartis Vaccines Institute for Global Health, Siena, Italy. Electronic address:

Background: Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM197 in participants of various ages in endemic countries in south and southeast Asia.

Methods: We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18-45 years, children aged 24-59 months, older infants aged 9-12 months, and infants aged 6-8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov, numbers NCT01229176 and NCT01437267.

Findings: 320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL [95% CI 67-190] to 208 U/mL [117-369]), children (201 U/mL [138-294] to 368 U/mL [234-580]), and older infants (179 U/mL [129-250] to 249 U/mL [130-477]). However, in children and older infants, a second dose of conjugate vaccine had no incremental effect on antibody titres and, at all ages, concentrations of antibodies increased substantially 6 months after vaccination (from 55 U/mL [33-94] to 63 U/mL [35-114] in adults, from 23 U/mL [15-34] to 51 U/mL [34-76] in children, and from 21 U/mL [14-31] to 22 U/mL [14-33] in older infants). Immune response in infants aged 6-8 weeks was lower than that in older participants and, 6 months after third vaccination, antibody concentrations were significantly higher than pre-vaccination concentrations in Filipino (21 U/mL [16-28] vs 2.88 U/mL [1.95-4.25]), but not Pakistani (3.76 U/mL [2.77-5.08] vs 2.77 U/mL [2.1-3.66]), infants. Vi-CRM197 was safe and well tolerated and did not induce any significant interference with EPI vaccines. No deaths or vaccine-related serious adverse events were reported throughout the studies.

Interpretation: Vi-CRM197 is safe and immunogenic in endemic populations of all ages. Given at 9 months of age, concomitantly with measles vaccine, Vi-CRM197 shows a promise for potential inclusion in EPI schedules of countries endemic for typhoid. An apparent absence of booster response and a reduction in antibody titres 6 months after immunisation should be further investigated, but data show that an immunogenic typhoid vaccine can be safely delivered to infants during EPI visits recommended by WHO.

Funding: Sclavo Vaccines Association and Regione Toscana.
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http://dx.doi.org/10.1016/S1473-3099(13)70241-XDOI Listing
February 2014

Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults.

PLoS One 2011 30;6(9):e25398. Epub 2011 Sep 30.

Center for the Evaluation of Vaccination, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

Background: Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults.

Methodology: Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine.

Principal Findings: All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship.

Conclusions: Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.

Trial Registration: ClinicalTrials.gov NCT01123941 NCT01193907.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025398PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184126PMC
January 2012

Conjugate vaccines for enteric fever: proceedings of a meeting organized in New Delhi, India in 2009.

J Infect Dev Ctries 2010 Jun 30;4(6):404-11. Epub 2010 Jun 30.

Novartis Vaccines Institute for Global Health, 53100 Siena, Italy.

Enteric fever is responsible for significant morbidity in South Asia and high prevalence of severe disease is seen in children under two years of age. Effective typhoid vaccines are available, but they cannot be used for children under two years of age and also have some limitations in older age groups. Participants supported development of a Salmonella Typhi conjugate vaccine able to induce effective, long-lasting immunity in young children. The role of Salmonella Paratyphi A as a cause of enteric fever was discussed and consensus reached that a bivalent S. Typhi-S. Paratyphi A conjugate vaccine is highly desirable; however, considering disease epidemiology and the advanced status of vaccine development, rapid introduction of monovalent S. Typhi conjugate vaccine into vaccination programs of South Asia was recommended. Prevention should be emphasized, available vaccines used, and efforts toward improving sanitation continued. Success of the new vaccine will depend on several factors, including delivery costs and governmental ability to adopt and implement suitable immunization programs. To ensure good immunization coverage, the conjugate vaccine could be administered either to young infants, concomitantly with infant EPI vaccines, or to older infants, concomitantly with measles vaccine, currently given at 9 to 12 months. The need for new combination vaccines, containing both EPI and typhoid antigens, was discussed as a tool to increase coverage and reduce the number of injections and priority conflicts in a crowded infant vaccination schedule. However, stand-alone enteric fever conjugate vaccines would allow more flexibility to immunize different age groups and therefore should be rapidly developed.
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June 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

Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant.

Pediatr Infect Dis J 2009 Jul;28(7):563-71

Vaccine Research Center, University of Tampere Medical School, Tampere, Finland.

Background: Children have high morbidity and hospitalization rates from seasonal influenza. Meta-analyses suggest that conventional inactivated influenza vaccines are of low efficacy in young children, making vaccines that induce greater and broader immune protection in this vulnerable population a medical priority. Adjuvanted influenza vaccines may offer a solution.

Subjects And Methods: Unprimed healthy children (6 to <36 months) were enrolled in an observer-blinded study and randomly assigned to receive 2 doses of MF59-adjuvanted vaccine (Sub/MF59, n = 130) or nonadjuvanted split vaccine (split, n = 139); subgroups of these (n = 43 and 46, respectively) received a booster dose 1 year later. Safety and clinical tolerability were assessed after each dose. Hemagglutination inhibition antibody titers were measured against influenza A and B strains included in the formulation of the vaccines and against mismatched strains.

Results: Clinical tolerability and safety were generally comparable between vaccine groups, though some transient, mild solicited reactions were more frequent in the Sub/MF59 group. Postvaccination hemagglutination inhibition antibody titers to all 3 vaccine strains were significantly higher with Sub/MF59 than with split vaccine (all comparisons P < 0.001) after each of the 3 vaccine doses. In addition, Sub/MF59 induced significantly higher cross-reactivity against A/H3N2 and A/H1N1 mismatched strains.

Conclusion: MF59-adjuvanted influenza vaccine was well tolerated in healthy young children after each of 3 doses and induced greater, longer-lasting, and broader immune responses than a nonadjuvanted split vaccine. The enhanced immunogenicity of the adjuvanted vaccine was most evident in very young children and for the B vaccine strain.
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http://dx.doi.org/10.1097/INF.0b013e31819d6394DOI Listing
July 2009

MF59-adjuvanted vaccines for seasonal and pandemic influenza prophylaxis.

Influenza Other Respir Viruses 2008 Nov;2(6):243-9

Novartis Vaccines, Marburg, Germany.

Influenza is a major cause of worldwide morbidity and mortality through frequent seasonal epidemics and infrequent pandemics. Morbidity and mortality rates from seasonal influenza are highest in the most frail, such as the elderly, those with underlying chronic conditions and very young children. Antigenic mismatch between strains recommended for vaccine formulation and circulating viruses can further reduce vaccine efficacy in these populations. Seasonal influenza vaccines with enhanced, cross-reactive immunogenicity are needed to address these problems and can confer a better immune protection, particularly in seasons were antigenic mismatch occurs. A related issue for vaccine development is the growing threat of pandemic influenza caused by H5N1 avian strains. Vaccines against strains with pandemic potential offer the best approach for reducing the potential impact of a pandemic. However, current non-adjuvanted pre-pandemic vaccines offer suboptimal immunogenicity against H5N1. For both seasonal and pre-pandemic vaccines, the addition of adjuvants may be the best approach for providing enhanced cross-reactive immunogenicity. MF59, the first oil-in-water emulsion licensed as an adjuvant for human use, can enhance vaccine immune responses through multiple mechanisms. A trivalent MF59-adjuvanted seasonal influenza vaccine (Fluad has shown to induce significantly higher immune responses to influenza vaccination in the elderly, compared with non-adjuvanted vaccines, and to provide cross-reactive immunity against divergent influenza strains. Similar results have been generated with a MF59-adjuvanted H5N1 pre-pandemic vaccine, which showed higher and broader immunogenicity compared with non-adjuvanted pre-pandemic vaccines.
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http://dx.doi.org/10.1111/j.1750-2659.2008.00059.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634121PMC
November 2008

MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults.

PLoS One 2009 6;4(2):e4384. Epub 2009 Feb 6.

Novartis Vaccines, Marburg, Germany.

Background: Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed.

Methods And Findings: Healthy adults aged 18-60 and > 60 years (n = 313 and n = 173, respectively) were randomized (1:1) to receive two primary and one booster injection of 7.5 microg or 15 microg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 microg and 15 microg doses were comparable. The rates for seroprotection (HI>40; SRH>25 mm(2); MN > or = 40) after the primary vaccination ranged 72-87%. Six months after primary vaccination with the 7.5 microg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 microg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations.

Conclusions: Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs.

Trial Registration: (ClinicalTrials.gov) NCT00311480.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004384PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634740PMC
March 2009

Safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine in elderly Chinese subjects.

Immun Ageing 2008 Feb 20;5. Epub 2008 Feb 20.

Centre for Vaccine Clinical Research, Center for Disease Prevention, 18 Jinzhou Street, 530022 Nanning City, China.

Background: The safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine (Sub/MF59; FLUAD, Novartis Vaccines) was evaluated among elderly Chinese subjects (> or = 60 years of age). After a preliminary Phase I, open-label study (n = 25) to assess safety 1-14 days post-vaccination, a comparative observer-blind, randomised, controlled clinical trial (n = 600) was performed to assess safety and immunogenicity versus a non-adjuvanted subunit influenza vaccine (Subunit; Agrippal, Novartis Vaccines). Subjects were randomised (2:1) to receive Sub/MF59 or Subunit.

Results: Both vaccines were well tolerated, with no vaccine-related serious adverse events reported during the Phase I trial. During the observer-blind study, local and systemic reactions were generally similar for both vaccines 1-22 days post-vaccination; however, injection-site induration was more frequent among the Subunit group (P < 0.05), and mild pain at the injection site and fever were more frequent among Sub/MF59 recipients (P < or = 0.005). Both vaccines induced a significant (P < 0.001) increase in geometric mean titres (GMTs) for the three strains tested, versus baseline; GMTs against A/H1N1, A/H3N2 and B were significantly higher in the Sub/MF59 group (P = 0.034, P < 0.001 and P = 0.005, respectively). GMT ratios against A/H1N1, A/H3N2 and B were also significantly higher in the Sub/MF59 group (P = 0.038, P < 0.001 and P = 0.006, respectively). Similarly, the percentage of subjects achieving seroprotection or seroconversion on Day 22 was greater for Sub/MF59 recipients, reaching significance for A/H3N2 (P < 0.001).

Conclusion: MF59-adjuvanted subunit influenza vaccine is well tolerated by elderly Chinese subjects and induces a higher level of immunogenicity than a non-adjuvanted subunit influenza vaccine in this population that is at high risk of influenza-related complications.

Clinical Trial Registry: http://www.clinicaltrials.gov, NCT00310648.
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http://dx.doi.org/10.1186/1742-4933-5-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291031PMC
February 2008

Vaccines with the MF59 adjuvant do not stimulate antibody responses against squalene.

Clin Vaccine Immunol 2006 Sep;13(9):1010-3

Research Center, Novartis Vaccines, Via Fiorentina 1, 53100 Siena, Italy.

Squalene is a naturally occurring oil which has been used in the development of vaccine adjuvants, such as the oil-in-water emulsion MF59. In past years, by use of noncontrolled and nonvalidated assays, a claim was made that antisqualene antibodies were detectable in the sera of individuals with the so-called Gulf War syndrome. Using a validated enzyme-linked immunosorbent assay for the quantitation of immunoglobulin G (IgG) and IgM antibodies against squalene, we demonstrated that antisqualene antibodies are frequently detectable at very low titers in the sera of subjects who were never immunized with vaccines containing squalene. More importantly, vaccination with a subunit influenza vaccine with the MF59 adjuvant neither induced antisqualene antibodies nor enhanced preexisting antisqualene antibody titers. In conclusion, antisqualene antibodies are not increased by immunization with vaccines with the MF59 adjuvant. These data extend the safety profile of the MF59 emulsion adjuvant.
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http://dx.doi.org/10.1128/CVI.00191-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1563566PMC
September 2006

Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers.

J Virol 2006 May;80(10):4962-70

Infectious Diseases Unit, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom.

Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-microg doses of hemagglutinin from each virus strain with either 3, 10, or 30 microg of heat-labile Escherichia coli enterotoxin (LTK63) and 990 microg of a supramolecular biovector; one intranasally vaccinated group was given 7.5-microg doses of hemagglutinin with 30 microg of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 microg hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 microg LTK63 with the biovector, occurring in 7/15 (47%; P=0.0103), 8/15 (53%; P=0.0362), and 14/15 (93%; P=0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 microg LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P=0.0491) and B/Guandong (P=0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated.
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http://dx.doi.org/10.1128/JVI.80.10.4962-4970.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472052PMC
May 2006

An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine.

Vaccine 2006 Apr 19;24(16):3063-5. Epub 2006 Jan 19.

Chiron Vaccines, Research Center and Clinical Research, Via Fiorentina 1, 53100 Siena, Italy.

To test whether inactivated influenza vaccines distributed during the 2003-2004 influenza season in the northern hemisphere were able to confer protection against the mismatched variant A/Fujian/411/2002 virus strain, we measured haemagglutination inhibiting (HI) antibodies in elderly subjects vaccinated with three inactivated vaccines against the homologous A/H3N2 vaccine strain (A/Panama) and against the mismatched A/Fujian strain. The results showed that, while 76 to 80% of elder people vaccinated with conventional vaccines had protected levels of antibodies against the A/Fujian heterovariant strain, those vaccinated with the MF59-adjuvanted vaccine have protective levels of antibodies in >98% of the cases. We conclude that MF59-adjuvanted vaccines confer protection also against influenza virus strains which are not fully matched with those included in the vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2006.01.015DOI Listing
April 2006

Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy.

J Infect Dis 2005 Apr 14;191(8):1210-5. Epub 2005 Mar 14.

Influenza Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Antigenically well-matched vaccines against highly pathogenic avian influenza H5N1 viruses are urgently required. Human serum samples after immunization with MF59 or nonadjuvanted A/duck/Singapore/97 (H5N3) vaccine were tested for antibody to 1997-2004 human H5N1 viruses. Antibody responses to 3 doses of nonadjuvanted vaccine were poor and were higher after MF59-adjuvanted vaccine, with seroconversion rates to A/HongKong/156/97, A/HongKong/213/03, A/Thailand/16/04, and A/Vietnam/1203/04 of 100% (P < .0001), 100% (P < .0001), 71% (P = .0004), and 43% (P = .0128) in 14 subjects, respectively, compared with 27%, 27%, 0%, and 0% in 11 who received nonadjuvanted vaccine. These findings have implications for the rational design of pandemic vaccines against influenza H5.
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http://dx.doi.org/10.1086/428948DOI Listing
April 2005

Intranasal immunization with genetically detoxified diphtheria toxin induces T cell responses in humans: enhancement of Th2 responses and toxin-neutralizing antibodies by formulation with chitosan.

Vaccine 2004 Feb;22(8):909-14

Immune Regulation Research Group, Department of Biochemistry, Trinity College, Dublin 2, Ireland.

We previously reported that intranasal immunization with a non-toxic mutant cross-reacting material (CRM)197 of diphtheria toxin, formulated with chitosan, generated protective neutralizing antibodies in mice and guinea pigs. Furthermore, we demonstrated that intranasal delivery of a powder formulation of the CRM197-based vaccine was well tolerated and significantly boosted antibody responses in adult volunteers. Here we report that intranasal booster immunization with CRM197 alone or with chitosan induced systemic T cell responses. We addressed for the first time the induction of T cell subtypes following intranasal vaccination in humans. Intranasal vaccination with CRM197, like parenteral immunization with a conventional diphtheria toxoid vaccine, enhanced antigen-specific IFN-gamma production. However, formulation of the nasal diphtheria vaccine with chitosan significantly augmented Th2-type responses, which correlated with protective levels of toxin-neutralizing antibodies in intranasally boosted individuals. The results suggest that vaccines capable of inducing strong Th2-type responses, such as CRM197 formulated with chitosan, have potential for the development of a protective mucosal vaccine against diphtheria in humans. Furthermore, our findings demonstrate that mucosal subunit vaccines with appropriate delivery systems have considerable potential for booster immunization of adults.
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http://dx.doi.org/10.1016/j.vaccine.2003.09.012DOI Listing
February 2004

Safety and immunogenicity of two Haemophilus influenzae type b conjugate vaccines.

S Afr Med J 2004 Jan;94(1):43-6

Department of Community Health, Medical University of Southern Africa, Pretoria.

Objectives: Haemophilus influenzae type b (Hib) infection remains a major public health problem in the developing world. We evaluated the safety and immunogenicity of a new PRP-CRM197 conjugate Hib vaccine (Vaxem Hib, Chiron Vaccines), compared with the HibTITER vaccine (Wyeth-Lederle Vaccines), following the World Health Organisation (WHO)'s accelerated schedule which allows 4-week intervals between doses.

Study Design: A phase II, observer-blind, multicentre, randomised, controlled, non-inferiority study.

Methods: In total, 331 babies were immunised with either Vaxem Hib (N = 167) or HibTITER (N = 164) vaccine at 6, 10 and 14 weeks of age, in parallel with oral polio, diphtheriatetanus-pertussis and hepatitis B vaccines. Post-immunisation reactions were recorded after each immunisation and at follow-up visits. Anti-polyribosylribitol phosphate (PRP) antibodies were measured using enzyme-linked immunosorbent assays (ELISAs) before and 1 month after the third immunisation.

Results: Overall, there was no significant difference in the anti-PRP levels between the two groups. One month after the third immunisation, 76% of vaccinees in the Vaxem Hib group and 70% in the HibTITER group had anti-PRP antibody titres > or = 1.0 microgram/ml, while 96% of the Vaxem Hib group and 90% of the HibTITER group demonstrated anti-PRP antibody titres > or = 0.15 microgram/ml. The geometric mean titre at day 90 was 3.77 micrograms/ml for the Vaxem Hib and 3.0 micrograms/ml for the HibTITER groups. Although the Vaxem Hib vaccine produced more redness (6% versus 1%; p = 0.006) and swelling (5% versus 1%, p = 0.037), overall it was well tolerated compared with the HibTITER vaccine. There was no significant difference in vaccine-related elevated temperature (> or = 38 degrees C) between the two groups (p = 0.11).

Conclusion: Both vaccines showed comparable safety and immunogenicity profiles when administered to South African babies at 6, 10 and 14 weeks of age.
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January 2004

Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults.

Vaccine 2003 Oct;21(27-30):4234-7

Saint Louis University School of Medicine, Saint Louis, MO, USA.

The adjuvanted influenza vaccine FLUAD is composed of subunit influenza antigens combined with the MF59-adjuvant emulsion. The vaccine was developed primarily for use in elderly populations, but non-elderly individuals might also benefit. To evaluate this hypothesis, 301 healthy adults were assigned randomly to receive two intramuscular injections of either FLUAD (150 subjects) or a non-adjuvanted vaccine, Fluzone (151 subjects), in two trials conducted at a 1-year interval. Injections consisted of 15 micrograms per 0.5 ml dose. Vaccine composition was A/Texas/36/91 (H1N1), A/Johannesburg/33/94 (H3N2), and B/Harbin/7/94 for the first injection and A/Texas/36/91 (H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/7/94 for the second injection. Immunogenicity was evaluated at 28 and 180 days post-immunization. FLUAD was generally well tolerated in healthy adults when compared with Fluzone. FLUAD was associated with increased pain at the injection site after immunization. A statistically significant increase in the incidence of injection-site warmth, chills, myalgia, and analgesic/antipyretic use occurred in the FLUAD group after the first injection but not after the second injection. In both groups, most of these local and systemic reactions were classified as mild. FLUAD was more immunogenic than Fluzone following both injections. After the first injection, statistically significant differences were found in the percentage of subjects with four-fold rises in hemagglutinin inhibition (HI) titers at 28 days post-immunization for the B antigen. After the second injection, the FLUAD group had significantly higher HI titers, a significantly higher percentage with a four-fold increase in titer, and a significantly greater percentage of subjects with titers >/=160 for the H3N2 antigen at 28 days. Only minor immunogenicity differences between the two groups were seen at 180 days. Compared with Fluzone, FLUAD was associated with increased immunogenicity and mild post-immunization reactions in healthy adults. The magnitude of increased immunogenicity in healthy adults was less than that seen in elderly populations.
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http://dx.doi.org/10.1016/s0264-410x(03)00456-0DOI Listing
October 2003

Antibody responses and HIV-1 viral load in HIV-1-seropositive subjects immunised with either the MF59-adjuvanted influenza vaccine or a conventional non-adjuvanted subunit vaccine during highly active antiretroviral therapy.

Vaccine 2003 Sep;21(25-26):3629-37

Department of Hygiene, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.

Objective: To study immunological and virological parameters in HIV-1-seropositive adults treated with highly active antiretroviral therapy (HAART) for at least 7 months after immunisation with MF59-adjuvanted (FLUAD, Chiron, Siena, Italy) or with non-adjuvanted (AGRIPPAL, Chiron) trivalent influenza vaccine.

Design: Blood samples, collected before and after vaccination, were analysed for the presence of antibodies against the vaccine antigens, for number of CD4+ T lymphocytes and HIV-1 RNA levels.

Results: Forty-four volunteers received FLUAD and 40 AGRIPPAL influenza vaccine. Thirty days after vaccination both adjuvanted and non-adjuvanted vaccines induced significant increases of anti-influenza virus antibodies. However, antibody titres found in volunteers receiving adjuvanted vaccine were in general significantly higher when compared with those found in the non-adjuvanted vaccine group. The requirements of the European Commission of influenza vaccine for a non-elderly adult population were always met by recipients of the adjuvanted vaccine, even in those with the lowest CD4+ cell counts (<200 cells/mmc). The subjects receiving the non-adjuvanted vaccine failed to met these requirements. The CD4+ T lymphocytes and plasma HIV-1 RNA levels remained stable in the long term, both in people receiving adjuvanted or non-adjuvanted vaccine.

Conclusion: MF59-adjuvanted influenza induced a significant higher immune responses as compared with conventional vaccine in HIV-seropositive HAART-treated patients. Both vaccines were safe regarding HIV RNA viral replication and loss of CD4+ T lymphocytes.
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http://dx.doi.org/10.1016/s0264-410x(03)00408-0DOI Listing
September 2003

Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines.

Expert Rev Vaccines 2003 Apr;2(2):285-93

IRIS Research Center, Department of Hygiene, Microbiology and Biostatistical Sciences, University of Modena and Reggio Emilia, Italy.

Cholera toxin and Escherichia coli heat-labile enterotoxin are powerful mucosal adjuvants but their high toxicity hampers their use in humans. Site-directed mutagenesis has allowed the generation of several cholera toxin and E. coli heat-labile enterotoxin mutants with abolished or strongly reduced toxicity that still retain strong mucosal adjuvanticity. Among them, LTK63 (Ser to Lys substitution at position 63 in the A subunit) is completely nontoxic and LTR72 (Ala to Arg at position 72) retains a very low residual enzymatic activity. Both of them have been shown to be safe and effective in enhancing the immunogenicity of intranasally coadministered vaccines, also resulting in protective responses in several animal models. Clinical grade preparations of these mutants have now been produced, tested in animals and proven to be totally safe. Indeed, they did not induce any inflammatory event in the respiratory tract nor, more importantly, in the olfactory bulbs and in the meninges. The fully nontoxic LTK63 mutant has now been successfully tested in human volunteers with a trivalent subunit influenza vaccine.
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http://dx.doi.org/10.1586/14760584.2.2.285DOI Listing
April 2003

MF59-adjuvanted vaccines: increased immunogenicity with an optimal safety profile.

Expert Rev Vaccines 2003 Apr;2(2):197-203

Chiron Vaccines Clinical Research & Medical Affairs, Siena, Italy.

The need to enhance the immunogenicity of purified subunit antigens has prompted the development of several new adjuvants. However, many of these new molecules have demonstrated a reactogenicity profile that is not suitable for their inclusion in vaccines for human use. In this context, the adjuvant emulsion MF59 has been developed, tested in combination with different antigens in several animal models and subsequently evaluated in humans. Clinical trials with several MF59-adjuvanted vaccines have been performed in different age groups (from newborns to the elderly) and have shown an increased immunogenicity of coadministered antigens, associated with a high level of safety and tolerability. MF59 has been the first adjuvant to be licensed for human use after alum and, as part of an enhanced influenza vaccine for the elderly, is now available in the marketplace of several countries worldwide.
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http://dx.doi.org/10.1586/14760584.2.2.197DOI Listing
April 2003

Effect of aluminum adjuvants on safety and immunogenicity of Haemophilus influenzae type b-CRM197 conjugate vaccine.

Pediatr Int 2003 Jun;45(3):314-8

Departments of Paediatric Infectious Diseases and Social Pediatrics Medical Faculty, Hacettepe University, Ankara, Turkey.

Objective: The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM197 (Hib-CRM197) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO4).

Methods: The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Gülveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days.

Results: Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO4 vaccine (19, 10, 11% in Chiron Hib/AlPO4, VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 micro g/mL, respectively (P < 0.05).

Conclusions: The use of aluminum compounds adjuvants in Hib-CRM197 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers.
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http://dx.doi.org/10.1046/j.1442-200x.2003.01706.xDOI Listing
June 2003

A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis.

Gerontology 2003 May-Jun;49(3):177-84

Clinical Research and Medical Affairs, Chiron Vaccines, Marburg, Germany.

Background: The elderly are at a higher risk of morbidity and mortality associated with influenza infection than younger adults, but get less protection from conventional vaccination.

Objective: We conducted a meta-analysis of all available data from clinical trials in the elderly on a recently introduced MF59-adjuvanted influenza vaccine to determine its immunogenicity and safety in subjects with underlying chronic disease who are at highest risk of influenza infection.

Methods: Data on immunogenicity and safety from 3600 subjects immunized with either the MF59-adjuvanted or conventional comparator influenza vaccine in 13 clinical trials were analyzed by disease history. Geometric mean haemagglutination inhibition titres (GMTs) and differences between the vaccine groups were compared using two-way analysis of variance. Differences between vaccine groups in the percentages with post-immunization reactions were assessed using chi-squared test and Fischer's exact test.

Results: At 28 days the adjuvanted:comparator GMT ratio for the A/H3N2 antigen was 1.18 in healthy elderly subjects and 1.43 in elderly subjects with chronic disease (p = 0.004). The respective GMT ratios were 1.17 versus 1.37 for the B antigen (p = 0.065) and 1.10 versus 1.17 for the A/H1N1 antigen (p = 0.41). Although post-immunization reactions were more common in the group receiving the adjuvanted vaccine, these were predominantly mild and transient, and none were serious.

Conclusions: The MF59-adjuvanted influenza vaccine is more immunogenic in elderly subjects than conventional non-adjuvanted influenza vaccines and especially so in those with chronic disease. Therefore, since its safety profile is clinically acceptable, this adjuvanted vaccine represents an excellent option for influenza immunization of elderly subjects at highest risk of complications.
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http://dx.doi.org/10.1159/000069172DOI Listing
August 2003

Boosting immunity to influenza H5N1 with MF59-adjuvanted H5N3 A/Duck/Singapore/97 vaccine in a primed human population.

Vaccine 2003 Apr;21(15):1687-93

Infectious Diseases Unit, Leicester Royal Infirmary, LE1 5WW, Leicester, UK.

In 1997, influenza A/Hong Kong/97 (H5N1) emerged as a potential human threat. In 1999, a randomised study comparing two doses of MF59-adjuvanted and non-adjuvanted influenza A/Duck/Singapore/97 (H5N3) surface-antigen vaccine found non-adjuvanted vaccine was poorly immunogenic. Addition of MF59 significantly boosted antibody to H5N1 to levels associated with protection. At 16 months, we undertook a follow-up study to assess the effect of H5N3 revaccination. Geometric mean titres (GMTs) of antibody by haemagglutination-inhibition (HI), microneutralisation (MN) and single radial haemolysis (SRH) indicated that protective antibody titres did not exist at 16 months after two-dose priming. Twenty-one days after revaccination, there was significant boosting of antibody compared to GMTs achieved 21 days after two-dose priming in the original study (P<0.001). MF59 significantly increased GMTs of antibody when compared to non-adjuvanted vaccine (P<0.001).
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http://dx.doi.org/10.1016/s0264-410x(02)00632-1DOI Listing
April 2003