-
Wellington Sun,
Kenneth H Eckels,
J Robert Putnak,
Arthur G Lyons,
Stephen J Thomas,
David W Vaughn,
Robert V Gibbons,
Stefan Fernandez,
Vicky J Gunther,
Mammen P Mammen,
John D Statler, Bruce L Innis
[show abstract]
[hide abstract]
ABSTRACT: Background. Protection against dengue requires immunity against all 4 serotypes of virus. Experimental challenge may be useful in evaluating vaccine-induced immunity.Methods. Ten subjects previously vaccinated with a live-attenuated tetravalent dengue vaccine (TDV) and 4 dengue naïve control subjects were inoculated subcutaneously (s.c.)with either 10(3) pfu's of Dengue-1 (DENV-1) or 10(5) pfu's of Dengue-3 (DENV-3) challenge viruses. Two additional subjects who did not develop DENV-3 neutralizing antibody (Nab) from TDV were re-vaccinated with 10(4) pfu's of live-attenuated DENV-3 vaccine to evaluate memory response.Results. All 5 TDV recipients were protected against DENV-1 challenge. Of the 5 TDV recipients challenged with DENV-3 2 were protected. All DENV-3 challenge subjects who developed viremia also developed elevated liver enzymes, 2 had values greater than 10 times normal. Of the 2 subjects revaccinated with DENV-3 vaccine 1 showed a secondary response to DENV-2 while neither showed such response to DENV-3. All 4 control subjects developed dengue fever from challenge. Protection was associated with presence of Nab though one subject was protected despite lack of measurable Nab at the time of DENV-1 challenge.Conclusions. Vaccination with live-attenuated TDV induced variable protection against s.c. challenge. DENV-3 experimental challenge was associated with transient but significant hepatitis.
The Journal of Infectious Diseases 12/2012; · 6.41 Impact Factor
-
Stephen J Thomas,
Kenneth H Eckels,
Isabelle Carletti,
Rafael De La Barrera,
Francis Dessy,
Stefan Fernandez,
Robert Putnak,
Jean-Francois Toussaint,
Wellington Sun,
Kristen Bauer,
Robert V Gibbons, Bruce L Innis
[show abstract]
[hide abstract]
ABSTRACT: Two formulations of a new live tetravalent dengue virus (DENV) vaccine produced using re-derived master seeds from a precursor vaccine and that same precursor vaccine as a control were compared in a placebo-controlled, randomized, observer-blind, phase II trial of 86 healthy adults. Two vaccine doses were administered 6 months apart; a third dose was offered to a subset. Symptoms and signs of dengue-like illness reported after vaccination were mild to moderate, transient, and occurred with similar frequency among recipients of the new DENV vaccine and placebo, except for rash. Neither dengue nor vaccine-related serious adverse events were reported. The first DENV vaccine dose was moderately immunogenic; the second dose increased the potency and breadth of the neutralizing antibody response. Tetravalent response rates to the new formulations were 60% and 66.7% in unprimed subjects. A third dose did not increase tetravalent antibody rates. The new DENV vaccine candidates merit additional evaluation.
The American journal of tropical medicine and hygiene 12/2012; · 2.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Live, multivalent vaccines have historically exhibited interference in humans; live dengue virus (DENV) vaccines have proven no exception.
To characterize interactions between DENV serotypes in a tetravalent live-attenuated virus vaccine candidate, we analyzed data from a factorial clinical trial in which all combinations of high- and low-dose DENV serotypes were combined in 16 live-attenuated tetravalent vaccine formulations (N = 64) and administered to flavivirus-naive adult volunteers. Regression models considered the outcomes of reactogenicity and seroconversion, controlling for all serotype doses simultaneously. Additionally, results were compared against earlier evaluations of the same viruses administered as monovalent formulations.
DENV-1 was immunologically dominant in both monovalent and tetravalent formulations. In tetravalent formulations, DENV-1 and DENV-2 antagonized each other, with a high dose of one decreasing seroconversion to the other. However, high-dose DENV-1 significantly increased seroconversion against 3 or more serotypes, increasing seroconversion to DENV-1, DENV-3, and DENV-4. The highest reactogenicity occurred when DENV-1 was at high dose and all others were low; reactogenicity decreased with the incorporation of other high-dose serotypes.
Interference and facilitation occurred between serotypes in the live vaccine candidate evaluated. These analyses suggest that it may be possible to exploit facilitation to increase overall seroconversion.
The Journal of Infectious Diseases 08/2011; 204(3):442-50. · 6.41 Impact Factor
-
Veerachai Watanaveeradej,
Sriluck Simasathien,
Ananda Nisalak,
Timothy P Endy,
Richard G Jarman, Bruce L Innis,
Stephen J Thomas,
Robert V Gibbons,
Sumetha Hengprasert,
Rudiwilai Samakoses,
Angkool Kerdpanich,
David W Vaughn,
J Robert Putnak,
Kenneth H Eckels,
Rafael De La Barrera,
Mammen P Mammen
[show abstract]
[hide abstract]
ABSTRACT: A Phase I/II observer-blind, randomized, controlled trial evaluated the safety and immunogenicity of a dengue virus (DENV) vaccine candidate in healthy Thai infants (aged 12-15 months) without measurable pre-vaccination neutralizing antibodies to DENV and Japanese encephalitis virus. Fifty-one subjects received two doses of either DENV (N = 34; four received 1/10th dose) or control vaccine (N = 17; dose 1, live varicella; dose 2, Haemophilus influenzae type b). After each vaccine dose, adverse events (AEs) were solicited for 21 days, and non-serious AEs were solicited for 30 days; serious AEs (SAEs) were recorded throughout the study. Laboratory safety assessments were performed at 10 and 30 days; neutralizing antibodies were measured at 30 days. The DENV vaccine was well-tolerated without any related SAEs. After the second dose, 85.7% of full-dose DENV vaccinees developed at least trivalent and 53.6% developed tetravalent neutralizing antibodies ≥ 1:10 to DENV (control group = 0%). This vaccine candidate, therefore, warrants continued development in this age group (NCT00322049; clinicaltrials.gov).
The American journal of tropical medicine and hygiene 08/2011; 85(2):341-51. · 2.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A trivalent inactivated influenza vaccine (Fluarix (™) , GlaxoSmithKline Biologicals) was licensed under US accelerated approval regulations. We performed a randomized, observer-blind, post-approval study to demonstrate its immunological non-inferiority versus an established US-licensed vaccine (primary endpoint). Adult (including elderly) subjects received a single injection of newly-licensed vaccine (n = 923) or established vaccine (n = 922). Serum hemagglutination-inhibition titers were determined pre-vaccination and 21-28 days after vaccination. Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio (upper 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper 95% CI ≤ 0.1) for all three vaccine strains. Safety was monitored for 6 months. The newly-licensed vaccine was non-inferior to the established vaccine in all subjects (≥ 18 years) and in elderly subjects (≥ 65 years). Adjusted GMT ratios (established/newly-licensed) against the H1N1, H3N2 and B strains were 0.65 (95% CI: 0.58, 0.73), 0.93 (0.83, 1.04) and 1.13 (1.03, 1.25) for all subjects and 0.75 (0.67, 0.85), 0.95 (0.82, 1.09) and 1.13 (1.00, 1.27) for elderly subjects. Corresponding values for the differences in seroconversion rate (established minus newly-licensed) were -0.12 (-0.16, -0.07), -0.02 (-0.06, 0.03) and 0.01 (-0.04, 0.06) for all subjects and -0.11 (-0.16, -0.05), -0.02 (-0.07, 0.04) and 0.02 (-0.04, 0.08) for elderly subjects. The most common adverse events with both vaccines were injection site pain, fatigue and headache, and no serious adverse events or deaths were considered related; there were no clinically relevant differences between the vaccines. In conclusion, the newly-licensed vaccine was well tolerated and immunologically non-inferior to the established vaccine for all three vaccine strains in the whole population and the elderly.
Human vaccines 01/2011; 7(1):81-8. · 3.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study (NCT00383123) compared the immunogenicity and safety of 2 trivalent inactivated influenza vaccines: Fluarix [GlaxoSmithKline (study vaccine)] and Fluzone [Sanofi Pasteur (control vaccine)] in children 6 months to <18 years.
Children, stratified by age and randomized, received either study (N = 2115) or control vaccine (N = 1210) at day 0 (and day 28 for previously unvaccinated children younger than 9 years). Children 6 months to <5 years comprised the according-to-protocol (ATP) cohort for immunogenicity, whereas the reactogenicity/safety group included all children 6 months to <18 years. The study aimed to demonstrate immunologic noninferiority of study vaccine versus control vaccine.
For children 6 months to <5 years, the predefined noninferiority criteria were not reached, mainly due to the differences in immune response in children 6 months to <3 years with no influenza vaccination history. All reactogenicity/safety endpoints were within the same range in both vaccine groups.
The study vaccine demonstrated a good safety and reactogenicity profile; however, it did not meet the predefined noninferiority criteria in children 6 months to <5 years. The study vaccine was as immunogenic as the control vaccine in children aged 3 to <5 years.
The Pediatric Infectious Disease Journal 10/2010; 29(10):924-30. · 3.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A new trivalent inactivated split-virus influenza vaccine (TIV) was recently introduced in the United States. We assessed the efficacy of TIV against culture-confirmed influenza A and/or B.
In this double-blind trial conducted from September 2006 to May 2007 in the Czech Republic and Finland, participants aged 18-64 years were randomized to receive 1 dose of TIV (n = 5103) or placebo (n = 2549). Influenza-like illnesses (ILI) (defined as at least 1 systemic symptom [fever {oral temperature, > or = 37.8 degrees C} and/or myalgia] and at least 1 respiratory symptom [cough and/or sore throat]) were identified by both active (biweekly phone contact) and passive surveillance. Nasal and throat swab specimens were collected for viral culture.
The attack rate for culture-confirmed ILI was 3.2% in the placebo group, with most strains identified as influenza A (all except 1 were H3N2) matching the vaccine strain. There were 6 cases of influenza B, all of which were of a different lineage (Yamagata) than the vaccine strain. Vaccine efficacy against culture-confirmed influenza A and/or B due to strains antigenically matched to the vaccine was 66.9% (95% confidence interval [CI], 51.9%-77.4%; P < .001) and to any strain was 61.6% (95% CI, 46.0%-72.8%; P < .001).
TIV is efficacious against culture-confirmed influenza in healthy adults.
ClinicalTrials.gov identifier: NCT00363870.
The Journal of Infectious Diseases 11/2009; 200(12):1861-9. · 6.41 Impact Factor
-
J Robert Putnak,
Rafael de la Barrera,
Timothy Burgess,
Jorge Pardo,
Francis Dessy,
Dirk Gheysen,
Yves Lobet,
Sharone Green,
Timothy P Endy,
Stephen J Thomas,
Kenneth H Eckels, Bruce L Innis,
Wellington Sun
[show abstract]
[hide abstract]
ABSTRACT: Plaque reduction neutralization tests (PRNTs) are commonly used for measuring levels of dengue virus (DENV) neutralizing antibodies. However, these assays lack a standardized format, generally have a low sample throughput, and are labor-intensive. The objective of the present study was to evaluate two alternative DENV neutralizing antibody assays: an enzyme-linked immunosorbent assay-based microneutralization (MN) assay, and a fluorescent antibody cell sorter-based, DC-SIGN expresser dendritic cell (DC) assay. False-positive rates, serotype specificity, reproducibility, sensitivity, and agreement among the assay methods were assessed using well-characterized but limited numbers of coded test sera. Results showed that all three assays had false-positive rates of less than 10% with titers near the cut-off and generally below the estimated limits of detection. All three methods demonstrated a high degree of specificity and good agreement when used to assay sera and serum mixtures from monovalent vaccinees and sera from patients after primary natural infection, with the only notable exception being moderate-to-high neutralizing antibody titers against DENV 2 measured by PRNT in a mixture containing only DENV 3 and DENV 4 sera. The MN and DC assays demonstrated good reproducibility. All three assays were comparable in their sensitivity, except that the PRNT was less sensitive for measuring DENV 4 antibody, and the MN and DC assays were less sensitive for measuring DENV 2 antibody. However, when used to test sera from persons after tetravalent DENV vaccination or secondary DENV infection, there was poor specificity and poor agreement among the different assays.
The American journal of tropical medicine and hygiene 08/2008; 79(1):115-22. · 2.59 Impact Factor
-
Sriluck Simasathien,
Stephen J Thomas,
Veerachai Watanaveeradej,
Ananda Nisalak,
Célia Barberousse, Bruce L Innis,
Wellington Sun,
J Robert Putnak,
Kenneth H Eckels,
Yanee Hutagalung,
Robert V Gibbons,
Chunlin Zhang,
Rafael De La Barrera,
Richard G Jarman,
Wipa Chawachalasai,
Mammen P Mammen
[show abstract]
[hide abstract]
ABSTRACT: A live-attenuated tetravalent dengue virus (DENV) vaccine candidate has been well tolerated and immunogenic in healthy, US flavivirus naive adult volunteers. We conducted a pilot, safety, and immunogenicity trial of the vaccine candidate in healthy Thai children (6-7 years of age) to prepare for its eventual evaluation in Thai infants. In an uncontrolled, open clinical trial, the investigational vaccine was administered on study Days 0 and 180 to seven volunteers residing in Bangkok without neutralizing antibodies to DENV1-4 or to Japanese encephalitis virus (JEV). Clinical and laboratory safety assessments were completed during the 30 days after each vaccine dose, and immunogenicity was determined at Day 30. In this study, the vaccine was well tolerated with no serious adverse events or alert laboratory values. One volunteer experienced fever (38.2 degrees C, < 2 days) and associated DENV4 vaccine viremia 7 days after Dose 2. One month after Dose 2, six volunteers in the per-protocol analysis exhibited a tetravalent neutralizing antibody response with DENV1-4 geometric mean titers of 55, 475, 350, and 171, respectively. Ten weeks (~75 days) after Dose 2, five of the six volunteers continued to exhibit a tetravalent neutralizing antibody profile; one volunteer's DENV4 PRNT50 titer fell below the assay cut-off (29 --> < 10); (clinicaltrials.gov NCT00384670).
The American journal of tropical medicine and hygiene 03/2008; 78(3):426-33. · 2.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To estimate the costs, benefits and cost-effectiveness of vaccination for rotavirus gastroenteritis in eight Latin American and Caribbean countries: Argentina, Brazil, Chile, the Dominican Republic, Honduras, Mexico, Panama, and Venezuela.
An economic model was constructed to estimate the cost-effectiveness of vaccination from the health care system perspective, using national administrative and published epidemiological evidence, country-specific cost estimates, and vaccine efficacy data. The model was applied to the first five years of life for the 2003 birth cohort in each country. The main health outcome was the disability-adjusted life year (DALY), and the main summary measure was the incremental cost per DALY averted. A 3% discount rate was used for all predicted costs and benefits. Sensitivity analyses evaluated the impact of uncertainty regarding key variables on cost-effectiveness estimates.
According to the estimates obtained with the economic model, vaccination would prevent more than 65% of the medical visits, deaths, and treatment costs associated with rotavirus gastroenteritis in the eight countries analyzed here. At a cost of US$ 24 per course (for a two-dose vaccine), the incremental cost-effectiveness ratio ranged from 269 US dollars/DALY in Honduras to 10,656 US dollars/DALY in Chile. Cost-effectiveness ratios were sensitive to assumptions about vaccine price, mortality, and vaccine efficacy.
Vaccination would effectively reduce the disease burden and health care costs of rotavirus gastroenteritis in the Latin American and Caribbean countries analyzed here. From the health care system perspective, universal vaccination of infants is predicted to be cost-effective, based on current standards.
Revista Panamericana de Salud Pública 05/2007; 21(4):205-16. · 0.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To estimate the health and economic burden of rotavirus gastroenteritis in hospital and outpatient settings in eight Latin American and Caribbean countries (Argentina, Brazil, Chile, Dominican Republic, Honduras, Mexico, Panama, and Venezuela).
An economic model was constructed using epidemiological data from published articles, national health administration studies, and country-specific cost estimates. For each of the eight countries, the model estimated the rotavirus outcomes for the 2003 birth cohort during the first five years of life. The main outcome measures included health care costs, transportation costs, lost wages, and disease burden expressed in disability-adjusted life years. Estimates were expressed in 2003 US dollars. All future costs and disability-adjusted life year estimates were discounted at a rate of 3%. Sensitivity analyses evaluated the impact of specific variables on the medical cost of treating rotavirus.
For every 1,000 children born during 2003 in the eight Latin American and Caribbean countries studied here, we estimated that rotavirus gastroenteritis would result in an average of 246 outpatient visits, 24 hospitalizations, 0.6 deaths, and 7,971 US dollars in direct medical costs during their first five years of life. The incidence of rotavirus-associated outpatient visits and the cost of outpatient visits were predicted to have the largest impact on the total medical cost per child.
Rotavirus gastroenteritis is likely to result in substantial disease and economic burden to health systems in Latin American and Caribbean countries, and the foreseeable burden should be an important consideration in evaluating the cost-effectiveness of vaccination.
Revista Panamericana de Salud Pública 05/2007; 21(4):192-204. · 0.85 Impact Factor
-
Mrigendra Prasad Shrestha,
Robert McNair Scott,
Durga Man Joshi,
Mammen P Mammen,
Gyan Bahadur Thapa,
Narbada Thapa,
Khin Saw Aye Myint,
Marc Fourneau,
Robert A Kuschner,
Sanjaya Kumar Shrestha,
Marie Pierre David,
Jitvimol Seriwatana,
David W Vaughn,
Assad Safary,
Timothy P Endy, Bruce L Innis
[show abstract]
[hide abstract]
ABSTRACT: Hepatitis E virus (HEV) is an important cause of viral hepatitis. We evaluated the safety and efficacy of an HEV recombinant protein (rHEV) vaccine in a phase 2, randomized, double-blind, placebo-controlled trial.
In Nepal, we studied 2000 healthy adults susceptible to HEV infection who were randomly assigned to receive three doses of either the rHEV vaccine or placebo at months 0, 1, and 6. Active (including hospital) surveillance was used to identify acute hepatitis and adverse events. The primary end point was the development of hepatitis E after three vaccine doses.
A total of 1794 subjects (898 in the vaccine group and 896 in the placebo group) received three vaccine doses; the total vaccinated cohort was followed for a median of 804 days. After three vaccine doses, hepatitis E developed in 69 subjects, of whom 66 were in the placebo group. The vaccine efficacy was 95.5% (95% confidence interval [CI], 85.6 to 98.6). In an intention-to-treat analysis that included all 87 subjects in whom hepatitis E developed after the first vaccine dose, 9 subjects were in the vaccine group, with a vaccine efficacy of 88.5% (95% CI, 77.1 to 94.2). Among subjects in a subgroup randomly selected for analysis of injection-site findings and general symptoms (reactogenicity subgroup) during the 8-day period after the administration of any dose, the proportion of subjects with adverse events was similar in the two study groups, except that injection-site pain was increased in the vaccine group (P=0.03).
In a high-risk population, the rHEV vaccine was effective in the prevention of hepatitis E. (ClinicalTrials.gov number, NCT00287469 [ClinicalTrials.gov].).
New England Journal of Medicine 04/2007; 356(9):895-903. · 53.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A cohort of 62 Nepalese adults with acute hepatitis E was identified and total Ig as well as IgM levels to hepatitis E virus (HEV) capsid protein were determined using the Walter Reed Army Institute of Research (WRAIR) immunoassay. An antibody profile was constructed from serial serum specimens collected up to 14 months following the onset of illness. The decline in total Ig was rapid for the first 3 months. There followed a slow, sustained decline, but antibodies remained above the seropositive level of 20 WRAIR units. The decline of IgM was steeper than total Ig for the first 3 months, but IgM remained detectable after 14 months in 25% of cases. Study data contribute to an understanding of the pathophysiology of human hepatitis E and set an antibody response pattern to be targeted as a part of HEV vaccine development.
Transactions of the Royal Society of Tropical Medicine and Hygiene 11/2006; 100(10):938-41. · 2.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Rhesus monkeys develop viremia after dengue virus (DENV) inoculation and have been used as an animal model to study DENV infection and DENV vaccine candidates. We evaluated, in this model, the protective efficacy of a live attenuated tetravalent DENV vaccine (TDV) candidate against parenteral challenge with parental near-wild-type DENV strains. Twenty monkeys were vaccinated with TDV at 0 and 1 month, and 20 unvaccinated monkeys served as controls. Vaccinated animals and their controls were inoculated with 10(3)-10(4) pfu of challenge virus 4.5 months after the second vaccination. Primary vaccination resulted in 95%, 100%, 70%, and 15% seroconversion to DENV serotypes 1, 2, 3, and 4 (DENV-1, -2, -3, and -4), respectively. After the second vaccination, the seropositivity rates were 100%, 100%, 90%, and 70%, respectively. Vaccination with TDV resulted in complete protection against viremia from DENV-2 challenge and in 80%, 80%, and 50% protection against challenge with DENV-1, -3, and -4, respectively. Our results suggest that the TDV can elicit protective immunity against all 4 DENV serotypes. Interference among the 4 vaccine viruses may have resulted in decreased antibody responses to DENV-3 and -4, which would require reformulation or dose optimization to minimize this interference during testing of the vaccine in humans.
The Journal of Infectious Diseases 07/2006; 193(12):1658-65. · 6.41 Impact Factor
-
Junkun He, Bruce L Innis,
Mrigendra P Shrestha,
Edward T Clayson,
Robert M Scott,
Kenneth J Linthicum,
Guy G Musser,
Scott C Gigliotti,
Leonard N Binn,
Robert A Kuschner,
David W Vaughn
Journal of Clinical Microbiology 04/2006; 44(3):1208. · 4.15 Impact Factor
-
Guillermo M Ruiz-Palacios,
Irene Pérez-Schael,
F Raúl Velázquez,
Hector Abate,
Thomas Breuer,
SueAnn Costa Clemens,
Brigitte Cheuvart,
Felix Espinoza,
Paul Gillard, Bruce L Innis, [......],
Juan Pablo Yarzábal,
Silvia Damaso,
Nadia Tornieporth,
Xavier Sáez-Llorens,
Rodrigo F Vergara,
Timo Vesikari,
Alain Bouckenooghe,
Ralf Clemens,
Béatrice De Vos,
Miguel O'Ryan
[show abstract]
[hide abstract]
ABSTRACT: The safety and efficacy of an attenuated G1P[8] human rotavirus (HRV) vaccine were tested in a randomized, double-blind, phase 3 trial.
We studied 63,225 healthy infants from 11 Latin American countries and Finland who received two oral doses of either the HRV vaccine (31,673 infants) or placebo (31,552 infants) at approximately two months and four months of age. Severe gastroenteritis episodes were identified by active surveillance. The severity of disease was graded with the use of the 20-point Vesikari scale. Vaccine efficacy was evaluated in a subgroup of 20,169 infants (10,159 vaccinees and 10,010 placebo recipients).
The efficacy of the vaccine against severe rotavirus gastroenteritis and against rotavirus-associated hospitalization was 85 percent (P<0.001 for the comparison with placebo) and reached 100 percent against more severe rotavirus gastroenteritis. Hospitalization for diarrhea of any cause was reduced by 42 percent (95 percent confidence interval, 29 to 53 percent; P<0.001). During the 31-day window after each dose, six vaccine recipients and seven placebo recipients had definite intussusception (difference in risk, -0.32 per 10,000 infants; 95 percent confidence interval, -2.91 to 2.18; P=0.78).
Two oral doses of the live attenuated G1P[8] HRV vaccine were highly efficacious in protecting infants against severe rotavirus gastroenteritis, significantly reduced the rate of severe gastroenteritis from any cause, and were not associated with an increased risk of intussusception. (ClinicalTrials.gov numbers, NCT00139347 and NCT00263666.)
New England Journal of Medicine 01/2006; 354(1):11-22. · 53.30 Impact Factor
-
J Robert Putnak,
Beth-Ann Coller,
Gerald Voss,
David W Vaughn,
David Clements,
Iain Peters,
Gary Bignami,
Hou-Shu Houng,
Robert C-M Chen,
David A Barvir,
Jitvimol Seriwatana,
Sylvie Cayphas,
Nathalie Garçon,
Dirk Gheysen,
Niranjan Kanesa-Thasan,
Mike McDonell,
Tom Humphreys,
Kenneth H Eckels,
Jean-Paul Prieels, Bruce L Innis
[show abstract]
[hide abstract]
ABSTRACT: The safety, immunogenicity, and protective efficacy of two non-replicating antigen-based vaccines and one live-attenuated virus (LAV) vaccine for dengue type-2 (dengue-2) virus were evaluated in the rhesus macaque model. The non-replicating vaccines consisted of whole, purified inactivated virus (PIV) and a recombinant subunit protein containing the amino-(N)-terminal 80% of envelope protein (r80E), each formulated with one of five different adjuvants. Each formulation was administered to three animals on a 0, 3-month schedule. Following the primary immunizations, 37 of 39 animals demonstrated dengue-2 virus neutralizing antibodies. After the booster immunizations all animals had dengue neutralizing antibodies with peak titers ranging from 1:100 to 1:9700. The highest neutralizing antibody titers were observed in the groups that received r80E antigen formulated with AS04, AS05, or AS08 adjuvant, and PIV formulated with AS05 or AS08 adjuvant. These newer adjuvants are based on alum, fraction QS-21 of saponin, and monophosphoryl lipid A (MPL). Protection was evaluated by dengue-2 virus challenge 2 months after the booster by the measurement of circulating virus (viremia) and post-challenge immune responses. Several groups exhibited nearly complete protection against viremia by bioassay, although there was evidence for challenge virus replication by Taqmantrade mark and immunological assays. None of the vaccines conferred sterile immunity.
Vaccine 09/2005; 23(35):4442-52. · 3.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Rotavirus is a major cause of gastroenteritis in children worldwide and is estimated to be responsible for more than 500,000 physician visits, 50,000 hospitalizations and 20 deaths in the United States each year.
To compare the safety and immunogenicity of 2 dosages of a live attenuated oral monovalent G1 human rotavirus (HRV) vaccine in healthy infants.
In this randomized, double blind trial conducted in the United States and Canada, 529 healthy infants 5-15 weeks of age received HRV vaccine containing either 10 or 10 focus-forming units or placebo. Two doses were administered orally at a 2-month interval concomitantly with routine childhood vaccines. Symptoms of fever, irritability/fussiness, diarrhea, vomiting, loss of appetite and cough/runny nose were solicited for 15 days postvaccination, nonserious adverse events for 43 days postvaccination and serious adverse events throughout the study. Vaccine take was defined as appearance of serum antirotavirus IgA in postimmunization sera at a titer of > or =20 units/mL or vaccine virus shedding in any stool sample collected between the first dose and 2 months after the second dose.
No serious adverse events considered related to vaccine were reported. The incidence of solicited symptoms was similar among treatment groups during the 15-day postvaccination surveillance periods. No significant difference in vaccine take after 2 doses (88.0% in high dose group and 81.5% in low dose group) was seen between vaccine groups (P = 0.153).
Two doses of either dosage level of HRV vaccine administered concurrently with routine childhood vaccines to healthy infants 5-15 weeks of age were well-tolerated and were highly immunogenic.
The Pediatric Infectious Disease Journal 06/2005; 24(6):481-8. · 3.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dengue (DENV) virus strains for each of the four DENV serotypes were modified by passage in primary dog kidney (PDK) cell cultures with final manufacture of vaccine lots in fetal rhesus monkey diploid cell cultures. "Strain sets" consisting of serially-passaged DENV were inoculated in rhesus monkeys along with unmodified parent viruses for each strain. Vaccine candidates were compared with unmodified parent viruses by measuring viremia and immune responses. All except one DENV-1 strain demonstrated reduced infection in monkeys after PDK cell passage. A DENV-3 strain lost all monkey infectivity after PDK cell passage. Twelve vaccine candidates were selected for Phase 1 human trials through this selection process.
The American journal of tropical medicine and hygiene 01/2004; 69(6 Suppl):12-6. · 2.59 Impact Factor
-
Wellington Sun,
Robert Edelman,
Niranjan Kanesa-Thasan,
Kenneth H Eckels,
J Robert Putnak,
Alan D King,
Huo-Shu Houng,
Douglas Tang,
John M Scherer,
Charles H Hoke, Bruce L Innis
[show abstract]
[hide abstract]
ABSTRACT: Four serotypes of monovalent live attenuated dengue virus vaccine candidates were tested for reactogenicity and immunogenicity in 49 flavivirus non-immune adult human volunteers. The four monovalent candidates were then combined into a tetravalent formulation and given to another 10 volunteers. Neutralizing antibody seroconversion rates after a single-dose monovalent vaccination ranged from 53% to 100%. Solicited reactogenicity was scored by each volunteer. A composite index, the Reactogenicity Index, was derived by these self-reported scores. Reactogenicity differed among the four serotype candidates with serotype-1 associated with the most vaccine related side effects. A second dose of monovalent vaccines at either 30 days or 90 days was much less reactogenic but did not significantly increase seroconversion rates. Seroconversion rates in the 10 volunteers who received a single dose of tetravalent vaccine ranged from 30% to 70% among the four serotypes. Similar to the monovalent vaccines, a second dose of the tetravalent vaccine at one month was less reactogenic and did not increase seroconversion. A third dose of the tetravalent vaccine at four months resulted in three of four volunteers with trivalent or tetravalent high-titer neutralizing antibody responses.
The American journal of tropical medicine and hygiene 01/2004; 69(6 Suppl):24-31. · 2.59 Impact Factor
