Melanie Saville - Academia.edu (original) (raw)

Papers by Melanie Saville

The Lancet

PEDIATRICS

Young children are at high risk for influenza-related complications. Vaccination of close househo... more Young children are at high risk for influenza-related complications. Vaccination of close household contacts is recommended to provide indirect protection to children <6 months of age. Studies have shown that live, cold-adapted influenza vaccine, trivalent, is efficacious in children. To assess the risks associated with inadvertent exposure of infants to vaccine viruses from vaccinated contacts, this study was designed to evaluate the safety and tolerability of cold-adapted influenza vaccine, trivalent, administered intranasally to healthy children 6 to <24 weeks of age. Healthy infants aged 6 to <16 weeks and 16 to <24 weeks, respectively, were randomly assigned to receive 2 doses of influenza vaccine, or placebo intranasally 35 +/- 7 days apart. Reactogenicity events were monitored for 11 days after each dose. Other adverse events were monitored through 28 to 35 days after dose 2. Of the infants aged 6 to <16 weeks, 31 received influenza vaccine and 28 received plac...

Influenza and Other Respiratory Viruses

Challenges facing seasonal and pandemic influenza vaccination include: increasing the immunogenic... more Challenges facing seasonal and pandemic influenza vaccination include: increasing the immunogenicity of seasonal vaccines for the most vulnerable, increasing vaccination coverage against seasonal influenza, and developing vaccines against pandemic strains that are immunogenic with very low quantities of antigen to maximize the number of people who can be vaccinated with a finite production capacity. We review Sanofi Pasteur's epidemic and pandemic influenza research and development programmes with emphasis on two key projects: intradermal influenza vaccine for seasonal vaccination of both elderly and younger adults, and pandemic influenza vaccine.

Vaccine, Jan 4, 2015

The most advanced dengue vaccine candidate is a live-attenuated recombinant vaccine containing th... more The most advanced dengue vaccine candidate is a live-attenuated recombinant vaccine containing the four dengue viruses on the yellow fever vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the vaccine. We analyse the immunogenicity data collected in five phase-2 trials of the CYD-TDV vaccine. We provide a descriptive analysis of the aggregated datasets and fit the observed post-vaccination PRNT50 titres against the four dengue (DENV) serotypes using multivariate regression models. We find that the responses to CYD-TDV are principally predicted by the baseline immunological status against DENV, but the trial is also a significant predictor. We find that the CYD-TDV vaccine generates similar titres against all serotypes following the third dose, though DENV4 is immunodominant after the f...

Revista Pan-Amazônica de Saúde, 2011

The Lancet, 2014

Background An estimated 100 million people have symptomatic dengue infection every year. This is ... more Background An estimated 100 million people have symptomatic dengue infection every year. This is the fi rst report of a phase 3 vaccine effi cacy trial of a candidate dengue vaccine. We aimed to assess the effi cacy of the CYD dengue vaccine against symptomatic, virologically confi rmed dengue in children.

Vaccine, 2011

Dengue vaccine development has reached a major milestone with the initiation, in 2010, of the fir... more Dengue vaccine development has reached a major milestone with the initiation, in 2010, of the first phase III clinical trial to investigate the Sanofi Pasteur CYD tetravalent dengue vaccine (TDV). The CYD TDV candidate is composed of four recombinant, live, attenuated vaccines (CYD-1-4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane and envelope genes of one of the four dengue virus serotypes. The vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D, and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies showed that CYD TDV induces controlled stimulation of human dendritic cells, and significant immune responses in monkeys. Scale up and industrialization are being conducted in parallel with preclinical and clinical development to fulfill the needs of phase II/III trials, and to anticipate and facilitate supply and access to vaccine in the countries where the dengue disease burden makes it an urgent public health priority. The vaccine has now been administered to more than 6000 children and adults from dengue endemic and non-endemic areas and no safety concerns have arisen in any of the completed or ongoing trials. A three-dose vaccination regimen induces an immune response against all four serotypes in the large majority of vaccinees. Preexisting flavivirus immunity favors quicker and higher immune responses to CYD TDV, without adversely effecting clinical safety or increasing vaccine viremia. The observed level and nature of the cellular immune responses in humans are consistent with the good safety and immunogenicity profile of the vaccine. Preliminary results of an ongoing, proof-ofconcept efficacy and large scale safety study in Thai children are expected by the end of 2012. Here we discuss the different steps and challenges of developing CYD TDV, from research to industrialization, and summarize some of the challenges to the successful introduction of a dengue vaccine into immunization programs. (B. Guy). efforts are focused on a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated dengue viruses (CYD-1-4) based on the yellow fever 17D vaccine strain (YFV 17D). This technology originated at the US National Institutes of Health and St Louis University and was further developed at Acambis, now part of Sanofi Pasteur . The live-attenuated and chimeric nature of these vaccine viruses necessitated extensive preclinical and clinical characterization, from the early stages of research through to the ongoing phase III clinical program and industrial development, taking into consideration the specific regulations pertaining to genetically modified organisms (GMO). Of note, a chimeric vaccine against Japanese encephalitis virus (JEV), which is similarly based on the YFV17D vaccine, has recently been licensed (IMOJEV TM , Sanofi Pasteur, Lyon France).

Vaccine, 2009

Avian influenza H7 viruses have transmitted from poultry to man causing human illness and fatalit... more Avian influenza H7 viruses have transmitted from poultry to man causing human illness and fatality, highlighting the need for pandemic preparedness against this subtype. We have developed and tested the first cell-based human vaccine against H7 avian influenza virus in a phase I clinical trial. Sixty healthy volunteers were intramuscularly vaccinated with two doses of split H7N1 virus vaccine containing 12 microg or 24 microg haemagglutinin alone or with aluminium hydroxide adjuvant (300 microg or 600 microg, respectively). The vaccine was well tolerated in all subjects and no serious adverse events occurred. The vaccine elicited low haemagglutination inhibition and microneutralisation titres, although the addition of aluminium adjuvant augmented the antibody response. We found a higher number of antibody secreting cells and an association with IL-2 production in subjects with antibody response. In conclusion, our study shows that producing effective H7 pandemic vaccines is as challenging as has been observed for H5 vaccines.

Sexually Transmitted Infections, 2000

To examine the "in use" test characteristics of the POCkit "near patie... more To examine the "in use" test characteristics of the POCkit "near patient" HSV-2 rapid test for the detection of HSV-2 IgG antibodies for use in the clinic. This test relies on a visual interpretation of the result. 2093 serum samples, 229 from UK and 919 from Italian genitourinary medicine clinic patients and 945 from obstetric and gynaecology clinic patients in Italy were tested. Tests were carried out according to manufacturers' protocol in the United Kingdom and Italy. Three readers independently recorded a score for each test carried out and the results were compared. In the UK study, the three readers disagreed on the result on 5.2% of tests. In the Italian study, there was disagreement in 10.2% of tests. This study has demonstrated a problem in the subjective nature of the interpretation of the POCkit HSV-2 test. It highlights the need for adequate training of clinic staff and the need for clinics to adopt policies of quality assurance and ongoing monitoring which will ensure the validity and accuracy of this clinic based test.

PEDIATRICS, 2006

OBJECTIVE. The goal was to evaluate the safety, tolerability, and efficacy of an investigational,... more OBJECTIVE. The goal was to evaluate the safety, tolerability, and efficacy of an investigational, refrigerator-stable formulation of live attenuated influenza vaccine (cold-adapted influenza vaccine-trivalent) against culture-confirmed influenza, acute otitis media, and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons.

The Pediatric Infectious Disease Journal, 2002

Influenza infections can cause severe respiratory disease in high risk persons such as those with... more Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children. To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma. In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre- to 28 days postvaccination. The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2% vs. 0.4% for the treatment and placebo groups, respectively; P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =15% from baseline, reductions in peak flows &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =15%, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =30% or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively; P = 1.0). No serious adverse event occurred. CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma.

The Pediatric Infectious Disease Journal, 2006

Live attenuated influenza vaccine (LAIV; FluMist) is a trivalent vaccine containing cold-adapted ... more Live attenuated influenza vaccine (LAIV; FluMist) is a trivalent vaccine containing cold-adapted influenza vaccine viruses that infect and replicate in cells lining the nasopharynx to induce immunity. Recovery of viruses (shedding) is measured by culture of nasal specimens. Shedding of vaccine viruses is not equated with transmission because transmission requires more virus than is detected in many nasal swabs. Previous studies with LAIV did not detect transmission to close contacts. The primary objective of this study was to estimate the probability of transmission to placebo contacts in a day care setting. One hundred ninety-seven healthy children aged 9 to 36 months attending day care were randomized to receive vaccine or placebo. Postvaccination viral shedding, safety, genotype and phenotype of shed viruses and probability of transmission were assessed. Eighty percent of 98 vaccine recipients shed at least one vaccine strain. No clinically significant differences in solicited adverse events attributable to vaccine occurred; safety profiles were similar in both groups. Vaccine virus isolates retained their phenotypic characteristics (cold adaptation and temperature sensitivity) and did not revert at nucleotides known to confer an attenuating phenotype. There was one confirmed transmission of a vaccine strain to a single placebo recipient. According to the Reed-Frost model, the calculated probability of transmission to a child after contact with a single vaccinated child was 0.58% (95% confidence interval, 0-1.7%). There was no increased reactogenicity or other safety concerns in the recipient child. Young children in a day care setting had a high rate of shedding and a low rate of transmission. No clinically significant illness occurred among children who received vaccine or placebo or in the child to whom the vaccine virus was transmitted.

The Lancet, 2006

Pathogenic avian influenza A virus H5N1 has caused outbreaks in poultry and migratory birds in As... more Pathogenic avian influenza A virus H5N1 has caused outbreaks in poultry and migratory birds in Asia, Africa, and Europe, and caused disease and death in people. Although person-to-person spread of current H5N1 strains is unlikely, the virus is a potential source of a future influenza pandemic. Our aim was to assess the safety and immunogenicity of a vaccine against the H5N1 strain. We did a randomised, open-label, non-controlled phase I trial in 300 volunteers aged 18-40 years and assigned one of six inactivated split influenza A/Vietnam/1194/2004 (H5N1) influenza vaccine formulations, comprising 7.5 microg (with adjuvant n=50, without adjuvant n=49), 15 microg (n=50, n=50), or 30 microg (n=51, n=50) of haemagglutinin with or without aluminium hydroxide adjuvant. Individuals received two vaccinations (on days 0 and 21) and provided blood samples (on days 0, 21, and 42) for analysis by haemagglutination inhibition and microneutralisation. We recorded all adverse events. Analyses were descriptive. All formulations were well tolerated, with no serious adverse events, few severe reactions, and no oral temperatures of more than 38 degrees C. All formulations induced an immune response, and responses were detectable in some individuals after only one dose. The adjuvanted 30 microg formulation induced the greatest response (67% haemagglutinin-inhibition seroconversion rate after two vaccinations). Adjuvant did not improve the response to the lower doses. Two vaccinations of non-adjuvanted 7.5 microg, adjuvanted 15 microg, or non-adjuvanted 15 microg seroconverted more than 40% of participants (haemagglutinin-inhibition test only). Haemagglutinin inhibition and neutralising results were comparable. A two-dose regimen with an adjuvanted 30 microg inactivated H5N1 vaccine was safe and showed an immune response consistent with European regulatory requirements for licensure of seasonal influenza vaccine. We noted encouraging responses with lower doses of antigen that need further study to ascertain their relevance for the choice of the final pandemic vaccine.

The Journal of Infectious Diseases, 2008

Enhanced influenza vaccines are needed to provide improved protection for elderly individuals. Th... more Enhanced influenza vaccines are needed to provide improved protection for elderly individuals. The intradermal vaccination route was hypothesized to provide immunogenicity superior to that provided by the intramuscular vaccination route.

Influenza and Other Respiratory Viruses, 2007

Influenza and Other Respiratory Viruses, 2008

Background The 2005 southern hemisphere formulation of the inactivated split-virion influenza vac... more Background The 2005 southern hemisphere formulation of the inactivated split-virion influenza vaccine Vaxigrip Ò unintentionally contained a lower concentration of haemagglutinin (HA) than European Pharmacopoeia (EP) and WHO specifications for one of the three strains. Objectives To evaluate the immunogenicity of the 2005 southern hemisphere formulation of an influenza vaccine containing 9 lg ⁄ dose of HA for A ⁄ Wellington ⁄ 1 ⁄ 2004(H3N2) strain, and 15 lg ⁄ dose for each of the A ⁄ New Caledonia ⁄ 20 ⁄ 99(H1N1) strain and B ⁄ Shanghai ⁄ 361 ⁄ 2002-like strains. Patients ⁄ ⁄ methods In an open, non-controlled multicentre clinical trial, 75 healthy adults (18-59 years) and 65 healthy older adults ( ‡60 years) were vaccinated once. Serum samples were obtained on D0 and 21 for haemagglutination inhibition (HAI) antibody titration.

Human Vaccines, 2010

The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of four recombinant live atte... more The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of four recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFv 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the Tv dengue vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFv 17D and does not infect mosquitoes by the oral route. in vitro and in vivo preclinical studies also showed that the Tv dengue vaccine induced controlled stimulation in human dendritic cells and significant immune responses in monkeys. Tv dengue vaccine reactogenicity, viramia induction and antibody responses were investigated in three Phase i trials in the USA, the Philippines and Mexico, in a two or three-dose regimen over a 12 month period. results showed that the majority of adverse events were mild to moderate and transient in nature. viremia was transient and low, and was not increased after initial dengue Tv administration, even in the case of incomplete responses. fSeropositivity (≥10 in a PrNT 50 assay) was 100% for all four serotypes in flavivirus-naive adults injected with 3 doses of Tv dengue vaccine in the USA. Similarly, seropositivity was 88-100% following three administrations in flavivirus-naive Mexican children aged 2-5 years. Furthermore, the proportion of seropositive subjects increased with each dengue Tv injection in the Philippines where baseline flavivirus immunity was high. responses were also monitored at the cellular level in humans, and their level and nature were in good agreement with the observed safety and the immunogenicity of the vaccine. Finally, the challenges inherent to the development of such Tv dengue vaccines will also be discussed in the last part of this review.

New England Journal of Medicine, 2015

Background A candidate tetravalent dengue vaccine is being assessed in three clinical trials invo... more Background A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries. We report the results of long-term follow-up interim analyses and integrated efficacy analyses. Methods We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials, CYD14 and CYD15, and a phase 2b trial, CYD23/57. We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15. Results Follow-up data were available for 10,165 of 10,275 participants (99%) in CYD14 and 19,898 of 20,869 participants (95%) in CYD15. Data were available for 3203 of the 4002 participants (80%) in the CYD23 trial included in CYD57. During year 3 in the CYD14, CYD15, and CYD57 trials combined, hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group. Pooled relative risks of hospitalization for dengue were 0.84 (95% confidence interval [CI], 0.56 to 1.24) among all participants, 1.58 (95% CI, 0.83 to 3.02) among those under the age of 9 years, and 0.50 (95% CI, 0.29 to 0.86) among those 9 years of age or older. During year 3, hospitalization for severe dengue, as defined by the independent data monitoring committee criteria, occurred in 18 of 22,177 participants in the vaccine group and 6 of 11,089 participants in the control group. Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3% (95% CI, 55.7 to 64.5) for all participants, 65.6% (95% CI, 60.7 to 69.9) for those 9 years of age or older, and 44.6% (95% CI, 31.6 to 55.0) for those younger than 9 years of age. Conclusions Although the unexplained higher incidence of hospitalization for dengue in year 3 among children younger than 9 years of age needs to be carefully monitored during long-term follow-up, the risk among children 2 to 16 years of age was lower in the vaccine group than in the control group. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530 , NCT01983553 , NCT01373281 , and NCT01374516 .).