Wyeth Vaccines Research

La Defense, France

Wyeth Vaccines Research

La Defense, France
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Lum L.C.S.,University of Malaya | Borja-Tabora C.F.,Manila Doctors Hospital | Breiman R.F.,International Center for Diarrhoeal Disease Research | Vesikari T.,University of Tampere | And 22 more authors.
Vaccine | Year: 2010

Children aged 11 to <24 months received 2 intranasal doses of live attenuated influenza vaccine (LAIV) or placebo, 35 ± 7 days apart. Dose 1 was administered concomitantly with a combined measles, mumps, and rubella vaccine (Priorix). Seroresponses to measles and mumps were similar between groups. Compared with placebo, response rates to rubella in LAIV + Priorix recipients were statistically lower at a 15 IU/mL threshold (83.9% vs 78.0%) and the prespecified noninferiority criteria were not met. In a post hoc analysis using an alternate widely accepted threshold of 10 IU/mL, the noninferiority criteria were met (93.4% vs 89.8%). Concomitant administration with Priorix did not affect the overall influenza protection rate of LAIV (78.4% and 63.8% against antigenically similar influenza strains and any strain, respectively). © 2009 Elsevier Ltd. All rights reserved.


Burckhardt I.,RWTH Aachen | Burckhardt I.,University of Heidelberg | Burckhardt F.,EPIET Alumnus | Van Der Linden M.,RWTH Aachen | And 3 more authors.
Epidemiology and Infection | Year: 2010

Pneumococcal meningitis is a subgroup of invasive pneumococcal disease with a case-fatality rate of up to 30% and long-term sequelae in more than 50% of cases in adults in developed countries. We aimed to determine risk factors for this particular form of pneumococcal disease. We conducted a prospective population-based laboratory study of invasive pneumococcal disease in adults in North-Rhine-Westphalia, Germany from February 2001 to August 2006. All isolates underwent serotyping and susceptibility testing at the National Reference Centre for Streptococci in Aachen, Germany. Data were analysed using multiple linear regression. A total of 1043 isolates from bacteraemia and 131 isolates from meningitis were included into the study. Serotype 23F and being female were independent risk factors for pneumococcal meningitis. Being 60 years and serotype 1 were associated with a reduced odds ratio. Season, penicillin and macrolide resistance were not statistically associated with CNS involvement. Copyright © 2010 Cambridge University Press.


Mascioni A.,Wyeth Research | Moy F.J.,Wyeth Research | McNeil L.K.,Wyeth Vaccines Research | Murphy E.,Wyeth Vaccines Research | And 13 more authors.
Biochimica et Biophysica Acta - Biomembranes | Year: 2010

Neisseria meningitidis is a major cause of meningitis. Although protective vaccination is available against some pathogenic serogroups, serogroup B meningococci have been a challenge for vaccinologists. A family of outer membrane lipoproteins, LP2086 (or factor H binding proteins, fHbp), has been shown to elicit bactericidal antibodies and is currently part of a cocktail vaccine candidate. The NMR structure of the variant LP2086-B01 in micellar solution provided insights on the topology of this family of proteins on the biological membrane. Based on flow cytometry experiments on whole meningococcal cells, binding experiments with monoclonal antibodies, and the NMR structure in micellar solution, we previously proposed that LP2086-B01 anchors the outer bacterial membrane through its lipidated N-terminal cysteine, while a flexible 20 residue linker positions the protein above the layer of lipo-oligosaccharides that surrounds the bacteria. This topology was suggested to increase the antigen exposure to the immune system. In the present work, using micellar solution as a membrane mimicking system, we characterized the backbone dynamics of the variant LP2086-B01 in both its lipidated and unlipidated forms. In addition, binding experiments with a Fab fragment derived from the monoclonal MN86-1042-2 were also performed. Our data suggests that due to the length and flexibility of the N-terminal linker, the antigen is not in contact with the micelle, thus making both N- and C-domains highly available to the host immune system. This dynamic model, combined with the binding data obtained with MN86-1042-2, supports our previously proposed arrangement that LP2086-B01 exposes one face to the extracellular space. Binding of MN86-1042-2 antibody shows that the N-domain is the primary target of this monoclonal, providing further indication that this domain is immunologically important for this family of proteins. © 2009 Elsevier B.V. All rights reserved.


Tribble D.R.,Naval Medical Research Center | Tribble D.R.,Bethesda University | Baqar S.,Naval Medical Research Center | Scott D.A.,Naval Medical Research Center | And 15 more authors.
Infection and Immunity | Year: 2010

A human Campylobacter jejuni infection model provided controlled exposure to assess vaccine efficacy and investigate protective immunity for this important diarrheal pathogen. A well-characterized outbreak strain, C. jejuni 81-176, was investigated using a volunteer experimental infection model to evaluate the dose range and. STV (25% of the subjects were not infected; 3-log-lower maximum excretion level). Systemic and mucosal immune responses were robust in naïve subjects irrespective of the dose or the severity of illness. In contrast, in STV there was a lack of circulating antibody-secreting cells (ASC), reflecting the local mucosal effector responses. LTV exhibited comparable ASC responses to primary infection, and anamnestic fecal IgA responses likely contributed to self-resolving illness prior to antibiotic treatment. Campylobacter antigen-dependent production of gamma interferon by peripheral blood mononuclear cells was strongly associated with protection from illness, supporting the hypothesis that TH1 polarization has a primary role in acquired immunity to C. jejuni. This study revealed a C. jejuni dose-related increase in campylobacteriosis rates, evidence of complete short-term protection that waned with time, and immune response patterns associated with protection. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Forrest B.D.,Wyeth Vaccines Research | Steele A.D.,University of Limpopo | Hiemstra L.,University of the Free State | Rappaport R.,Wyeth Vaccines Research | And 2 more authors.
Vaccine | Year: 2011

Background: Although influenza is a major public health concern among adults ≥60 years of age, few large, prospective studies of influenza vaccines have been conducted in this population. The goal of the present study was to directly compare the safety and efficacy of LAIV and TIV in adults ≥60 years of age. Materials and methods: A prospective, randomized, open-label, multicenter trial was conducted in South Africa. In March-April 2002, 3009 community-dwelling ambulatory adults 60-95 years of age were randomized 1:1 to receive a single dose of LAIV or TIV. Surveillance for influenza illness was conducted through November. Serum antibody titers were evaluated in all participants, and interferon-γ enzyme-linked immunosorbent spot assay responses were evaluated in a cohort of subjects. Solicited reactogenicity and adverse events were monitored for days 0-10 postvaccination; serious adverse events were monitored for the entire study. Results: Influenza illness caused by vaccine-matched strains was detected in 0.8% (12/1494) and 0.5% (8/1488) of LAIV and TIV recipients, respectively; the relative efficacy of LAIV vs TIV was -49% (95% CI: -259, 35). As expected, greater serum antibody responses were seen with TIV, and greater cellular responses were seen with LAIV (although not for influenza B). Among subjects with culture-confirmed influenza illness, post hoc analyses revealed trends toward less feverishness (LAIV, 14%; TIV, 46%; P= 0.05) and less fever (LAIV, 9%; TIV, 31%; P= 0.16) among LAIV recipients. In each treatment group, 38-39% and 24-25% of subjects had baseline hemagglutination inhibition titers of ≤4 for A/H1 and A/H3, but 7 of 8 TIV cases and 7 of 12 LAIV cases of matched-strain influenza occurred among these subjects. Runny nose/nasal congestion (+13%), cough (+5%), sore throat (+5%), lethargy (+3%), and decreased appetite (+2%) were reported by more LAIV vs TIV recipients. Injection site reactions were reported by 27% of TIV recipients. SAEs were reported by a similar proportion of LAIV and TIV recipients (9% vs 8%). Conclusions: Given the low incidence of influenza in both groups, no conclusions were possible regarding the relative efficacy of LAIV and TIV. There was a trend toward less feverishness/fever among LAIV recipients who developed influenza compared with TIV recipients with influenza, consistent with results from studies comparing the vaccines in children. A disproportionate number of influenza illnesses occurred among baseline seronegative subjects, particularly for those receiving TIV, which suggests that this subgroup has the greatest need for improved influenza vaccination. The safety profiles of LAIV and TIV were consistent with results from previous studies in older adults and no significant safety concerns were identified.clinicaltrials.gov identifier, NCT00192413. © 2011 Elsevier Ltd.


Zhou D.X.M.,Fudan University | Zhou D.X.M.,Chinese University of Hong Kong | Chan P.K.S.,Chinese University of Hong Kong | Zhang T.,Fudan University | And 3 more authors.
Virus Research | Year: 2010

Studies on the association between sequence variability of the interferon sensitivity-determining region (ISDR) of hepatitis C virus and the outcome of treatment have reached conflicting results. In this study, 25 patients infected with HCV 6a who had received interferon-alpha/ribavirin combination treatment were analyzed for the sequence variations. 14 of them had the full genome sequences obtained from a previous study, whereas the other 11 samples were sequenced for the extended ISDR (eISDR). This eISDR fragment covers 192. bp (64 amino acids) upstream and 201. bp (67 amino acids) downstream from the ISDR previously defined for HCV 1b. The comparison between interferon-alpha resistance and response groups for the amino acid mutations located in the full genome (6 and 8 patients respectively) as well as the mutations located in the eISDR (10 and 15 patients respectively) showed that the mutations I2160V, I2256V, V2292I (P<0.05) within eISDR were significantly associated with resistance to treatment. However, the extent of amino acid variations within previously defined ISDR was not associated with resistance to treatment as previously reported. Four amino acid variations I248V (P=0.03-0.06) within E1, R445K (P=0.02-0.05) and S747T (P=0.03) within E2, I861V (P=0.01) within NS2 which located outside the eISDR may also associate with treatment outcome as identified by a prescreening of variations within 14 HCV 6a full genomes. © 2010 Elsevier B.V.


Bryant K.A.,University of Louisville | Block S.L.,Kentucky Pediatric Adult Research | Baker S.A.,Wyeth Vaccines Research | Gruber W.C.,Wyeth Vaccines Research | Scott D.A.,Wyeth Vaccines Research
Pediatrics | Year: 2010

OBJECTIVE: Invasive pneumococcal disease rates have declined since immunization with 7-valent pneumococcal conjugate vaccine (PCV7) (Prevenar/Prevnar [Wyeth Pharmaceuticals, Philadelphia, PA]) became routine. Certain nonvaccine Streptococcus pneumoniae serotypes (1, 3, 5, 6A, 7F, and 19A) still cause significant morbidity and mortality. The safety and immunogenicity of PCV7 were compared with those of 13-valent PCV (PCV13), which contains saccharides from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F conjugated to CRM197. PATIENTS AND METHODS: Infants were randomly assigned to receive PCV13 or PCV7 at ages 2, 4, and 6 months with other vaccines. Post-third-dose antibodies to each pneumococcal polysaccharide were measured by immunoglobulin G enzyme-linked immunosorbent assay. Antibacterial functional antibodies were measured by opsonophagocytic assay (OPA). RESULTS: Subjects received PCV13 (n = 122) or PCV7 (n = 127). All PCV13 serotypes were immunogenic, with 88% to 98% of infants achieving antibody concentrations of ≥0.35 μg/mL to shared PCV7 serotypes. For the 6 additional serotypes, 97% to 100% of PCV13-vaccinated infants achieved antibody concentrations of ≥0.35 μg/mL. Geometric mean antibody concentration for PCV13 recipients ranged from 1.32 μg/mL (serotype 23F) to 4.26 μg/mL (serotype 14). The ratio of OPA geometric mean titers for the 7 shared serotypes (PCV13:PCV7) ranged from 0.6 to 1.4, suggesting no clinically meaningful differences. For PCV13-only serotypes, OPA geometric mean titers were significantly higher in the PCV13 group than in the PCV7 group. Local reactions and systemic events were similar between groups. CONCLUSIONS: PCV13 was well tolerated and immunogenic, with most infants developing antipolysaccharide antibody concentrations of ≥0.35 μg/mL, as well as OPA responses, to each of the 13 serotypes. Copyright © 2010 by the American Academy of Pediatrics.


Imohl M.,RWTH Aachen | Reinert R.R.,RWTH Aachen | Reinert R.R.,Wyeth Vaccines Research | Mutscher C.,RWTH Aachen | Van Der Linden M.,RWTH Aachen
BMC Microbiology | Year: 2010

Background: Macrolide resistant Streptococcus pneumoniae has been on a gradual increase in Germany for over a decade. The current study was undertaken against the background of the recent observation of declining macrolide resistance rates especially among German children. Nationwide surveillance of invasive pneumococcal disease has been conducted in Germany since 1992. A population- and laboratory-based approach was used to collect data on invasive pneumococcal disease, and isolates sent to the National Reference Center for Streptococci by diagnostic microbiological laboratories from 1992 to 2008 were included in this study. Results. From 1992 to 2008, data on macrolide susceptibility were available for 11,807 invasive isolates. 8,834 isolates (74.8%) were from adults ( 16 years), and 2,973 isolates (25.2%) from children (< 16 years). The overall nonsusceptibility rate of all isolates was 16.2% (intermediate, 0.2%; resistant, 16.0%). Higher resistance rates were observed among children (intermediate, 0.2%; resistant, 23.8%) than among adults (intermediate, 0.3%; resistant 13.4%). Maximum nonsusceptibility rates during the period under study were observed in 2005 (children: intermediate, 0.3%; resistant, 32.3%; adults: intermediate, 0.0%; resistant, 18.6%), while nonsusceptibility rates in 2008 were considerably lower, especially for children (children: intermediate, 0.0%; resistant, 15.2%; adults: intermediate, 0.1%; resistant, 12.9%). The rate of resistance was higher among the vaccine serotypes (7-valent, 36.6%; 10-valent, 28.2%; 13-valent, 24.3%) than among the non vaccine serotypes (non 7-valent, 6.5%; non 10-valent, 7.4%; non 13-valent, 6.3%). Serotype 14 (69.6% nonsusceptibility) proved to be the most resistant serotype. Conclusions. There has been a considerable and statistically significant decrease in macrolide nonsusceptibility in Germany since 2005, especially among children. © 2010 Imöhl et al; licensee BioMed Central Ltd.


Imohl M.,RWTH Aachen | Reinert R.R.,RWTH Aachen | Reinert R.R.,Wyeth Vaccines Research | Van Der Linden M.,RWTH Aachen
International Journal of Microbiology | Year: 2010

Nationwide surveillance of invasive pneumococcal disease has been conducted in Germany since 1992. From 1992 to 2008, a total of 12,137 isolates frominvasive pneumococcal disease were collected. Data on serotypes were available for 9,394 invasive isolates. The leading serotypes were serotypes 14 (16.5%), 3 (8.0%), 7F (7.6%), 1 (7.3%), and 23F (6.0%). Variations in serotype distribution over the years are particularly extensive, especially concerning serotype 14 (min 7.4%, max 33.5%) with the highest percentages among the isolates serotyped from around 1997 to 2006. Serotypes 1 and 7F increased over the last decade. No increase was observed concerning serotype 19A. Higher pneumococcal conjugate vaccine coverages were observed among children (7v, 57.3%; 10v, 72.8%; 13v, 83.5%) than among adults (7v, 39.9%; 10v, 55.5%; 13v, 73.5%). The temporal variations in serotype distribution have to be kept in mind when interpreting vaccine coverages reported in epidemiological studies. Copyright © 2010 Matthias Imöhl et al.


Although influenza is a major public health concern among adults 60 years of age, few large, prospective studies of influenza vaccines have been conducted in this population. The goal of the present study was to directly compare the safety and efficacy of LAIV and TIV in adults 60 years of age.A prospective, randomized, open-label, multicenter trial was conducted in South Africa. In March-April 2002, 3009 community-dwelling ambulatory adults 60-95 years of age were randomized 1:1 to receive a single dose of LAIV or TIV. Surveillance for influenza illness was conducted through November. Serum antibody titers were evaluated in all participants, and interferon- enzyme-linked immunosorbent spot assay responses were evaluated in a cohort of subjects. Solicited reactogenicity and adverse events were monitored for days 0-10 postvaccination; serious adverse events were monitored for the entire study.Influenza illness caused by vaccine-matched strains was detected in 0.8% (12/1494) and 0.5% (8/1488) of LAIV and TIV recipients, respectively; the relative efficacy of LAIV vs TIV was -49% (95% CI: -259, 35). As expected, greater serum antibody responses were seen with TIV, and greater cellular responses were seen with LAIV (although not for influenza B). Among subjects with culture-confirmed influenza illness, post hoc analyses revealed trends toward less feverishness (LAIV, 14%; TIV, 46%; P=0.05) and less fever (LAIV, 9%; TIV, 31%; P=0.16) among LAIV recipients. In each treatment group, 38-39% and 24-25% of subjects had baseline hemagglutination inhibition titers of 4 for A/H1 and A/H3, but 7 of 8 TIV cases and 7 of 12 LAIV cases of matched-strain influenza occurred among these subjects. Runny nose/nasal congestion (+13%), cough (+5%), sore throat (+5%), lethargy (+3%), and decreased appetite (+2%) were reported by more LAIV vs TIV recipients. Injection site reactions were reported by 27% of TIV recipients. SAEs were reported by a similar proportion of LAIV and TIV recipients (9% vs 8%).Given the low incidence of influenza in both groups, no conclusions were possible regarding the relative efficacy of LAIV and TIV. There was a trend toward less feverishness/fever among LAIV recipients who developed influenza compared with TIV recipients with influenza, consistent with results from studies comparing the vaccines in children. A disproportionate number of influenza illnesses occurred among baseline seronegative subjects, particularly for those receiving TIV, which suggests that this subgroup has the greatest need for improved influenza vaccination. The safety profiles of LAIV and TIV were consistent with results from previous studies in older adults and no significant safety concerns were identified. clinicaltrials.gov identifier, NCT00192413.

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