85 results on '"Raviprakash K"'
Search Results
2. A 200Gb/s Low Power DSP-Based Optical Receiver and Transmitter with Integrated TIA and Laser Drivers
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Zafrany, A., primary, Burgos, D., additional, Cai, L., additional, Chong, S., additional, Cramm, C., additional, Dadash, S., additional, Giridharan, V., additional, Gurumoorthy, V., additional, Helal, B., additional, Ho, C., additional, Iyer, A., additional, Jantzi, S., additional, Loi, C., additional, Nguyen, T., additional, Parker, K., additional, Pillai, E., additional, Raviprakash, K., additional, Ray, S., additional, Rossi, P., additional, Sun, Z., additional, Tan, A., additional, Tse, L., additional, Wall, B., additional, Wang, L., additional, Wang, J., additional, and Wu, T., additional
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- 2023
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3. A Log Log Law for Subsequences of Delayed Random Sums
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Divanji, Gooty and Raviprakash, K. N.
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- 2017
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4. 8.7 A 112Gb/s ADC-DSP-Based PAM-4 Transceiver for Long-Reach Applications with >40dB Channel Loss in 7nm FinFET
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Mishra, P., primary, Tan, A., additional, Helal, B., additional, Ho, C.R., additional, Loi, C., additional, Riani, J., additional, Sun, J., additional, Mistry, K., additional, Raviprakash, K., additional, Tse, L., additional, Davoodi, M., additional, Takefman, M., additional, Fan, N., additional, Prabha, P., additional, Liu, Q., additional, Wang, Q., additional, Nagulapalli, R., additional, Cyrusian, S., additional, Jantzi, S., additional, Scouten, S., additional, Dusatko, T., additional, Setya, T., additional, Giridharan, V., additional, Gurumoorthy, V., additional, Karam, V., additional, Liew, W., additional, Liao, Y., additional, and Ou, Y., additional
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- 2021
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5. Protective efficacy of a dengue 2 DNA vaccine in mice and the effect of CpG immuno-stimulatory motifs on antibody responses
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Porter, K. R., Kochel, T. J., Wu, S.-J., Raviprakash, K., Phillips, I., and Hayes, C. G.
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- 1998
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6. A dengue virus serotype-1 DNA vaccine induces virus neutralizing antibodies and provides protection from viral challenge in Aotus monkeys
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Kochel, T.J, Raviprakash, K, Hayes, C.G, Watts, D.M, Russell, K.L, Gozalo, A.S, Phillips, I.A, Ewing, D.F, Murphy, G.S, and Porter, K.R
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- 2000
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7. Immunogenicity of dengue virus type 1 DNA vaccines expressing truncated and full length envelope protein
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Raviprakash, K., Kochel, T.J., Ewing, D., Simmons, M., Phillips, I., Hayes, C.G., and Porter, K.R.
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- 2000
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8. MULTIPLE SPECIES OF THIONUCLEOSIDES IN RAGI (ELEUSINE CORACANA) tRNA
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RAVIPRAKASH, K. S. and CHERAYIL, JOSEPH D.
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- 1984
9. A 28 nm, 475 mW, and 0.4–1.7 GHz Embedded Transceiver Front-End Enabling High-Speed Data Streaming Within Home Cable Networks
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Spiridon, S., primary, Koh, D., additional, Xiao, J., additional, Brandolini, M., additional, Shen, B., additional, Hsiao, C.-M., additional, Huang, H., additional, Guermandi, D., additional, Bozzola, S., additional, Yan, H., additional, Introini, M., additional, Krishnan, L., additional, Raviprakash, K., additional, Shin, Y., additional, Gomez, R., additional, and Chang, J., additional
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- 2017
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10. A 28 nm, 475 mW, 0.4-to-1.7 GHz embedded transceiver front-end enabling high-speed data streaming within home cable networks
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Spiridon, S., primary, Koh, D., additional, Xiao, J., additional, Brandolini, M., additional, Shen, B., additional, Hsiao, C.-M., additional, Huang, H., additional, Guermandi, D., additional, Bozzola, S., additional, Yan, H., additional, Introini, M., additional, Krishnan, L., additional, Raviprakash, K., additional, Shin, Y., additional, Gomez, R., additional, and Chang, J., additional
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- 2016
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11. Reduced area discrete-time down-sampling filter embedded with windowed integration samplers
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Raviprakash, K., primary, Saad, R., additional, and Hoyos, S., additional
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- 2010
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12. Evaluation of immunity and protective efficacy of a dengue-3 premembrane and envelope DNA vaccine in Aotus nancymae monkeys
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BLAIR, P, primary, KOCHEL, T, additional, RAVIPRAKASH, K, additional, GUEVARA, C, additional, SALAZAR, M, additional, WU, S, additional, OLSON, J, additional, and PORTER, K, additional
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- 2006
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13. Characterization of antibody responses to combinations of a dengue-2 DNA and dengue-2 recombinant subunit vaccine.
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Simmons, M, primary, Hayes, C G, additional, Kochel, T, additional, Raviprakash, K, additional, and Murphy, G S, additional
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- 2001
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14. Conversion of dengue virus replicative form RNA (RF) to replicative intermediate (RI) by nonstructural proteins NS-5 and NS-3.
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Raviprakash, K, primary, Porter, K R, additional, Hayes, C G, additional, and Sinha, M, additional
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- 1998
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15. Inhibition of dengue virus by novel, modified antisense oligonucleotides
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Raviprakash, K, primary, Liu, K, additional, Matteucci, M, additional, Wagner, R, additional, Riffenburgh, R, additional, and Carl, M, additional
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- 1995
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16. Effects of deletions in the carboxy-terminal hydrophobic region of herpes simplex virus glycoprotein gB on intracellular transport and membrane anchoring
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Rasile, L, primary, Ghosh, K, additional, Raviprakash, K, additional, and Ghosh, H P, additional
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- 1993
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17. Acid pH-induced fusion of cells by herpes simplex virus glycoproteins gB an gD.
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Butcher, M, primary, Raviprakash, K, additional, and Ghosh, H P, additional
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- 1990
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18. Shortened cytoplasmic domain affects intracellular transport but not nuclear localization of a viral glycoprotein.
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Raviprakash, K, primary, Rasile, L, additional, Ghosh, K, additional, and Ghosh, H P, additional
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- 1990
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19. The mouse adenovirus type 1 contains an unusual E3 region
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Raviprakash, K S, Grunhaus, A, el Kholy, M A, and Horwitz, M S
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Since the E3 region of human adenoviruses codes for a series of proteins that are probably involved in viral pathogenesis, the nucleotide sequence for a 3.6-kilobase DNA fragment in the corresponding region (map units 77 through 89) of the mouse adenovirus type 1 genome has been determined. Analysis of the sequence revealed that the genes for the fiber and for the precursor to the hexon-associated protein, pVIII, that usually flank the E3 region, are well conserved. However, many of the open reading frames contained in the E3 region of human adenoviruses between the pVIII and the fiber genes were absent from the mouse adenovirus type 1 genome.
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- 1989
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20. Sex worker-led structural interventions in India: a case study on addressing violence in HIV prevention through the Ashodaya Samithi collective in Mysore.
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Reza-Paul, Sushena, Lorway, Rob, O'Brien, Nadia, Lazarus, Lisa, Jain, Jinendra, Bhagya, M., P., Fathima Mary, K. T., Venukumar, Raviprakash, K. N., Baer, James, and Steen, Richard
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AIDS , *HIV , *SEX workers , *SEXUALLY transmitted diseases - Abstract
Background & objectives: Structural interventions have the capacity to improve the outcomes of HIV/ AIDS interventions by changing the social, economic, political or environmental factors that determine risk and vulnerability. Marginalized groups face disproportionate barriers to health, and sex workers are among those at highest risk of HIV in India. Evidence in India and globally has shown that sex workers face violence in many forms ranging from verbal, psychological and emotional abuse to economic extortion, physical and sexual violence and this is directly linked to lower levels of condom use and higher levels of sexually transmitted infections (STIs), the most critical determinants of HIV risk. We present here a case study of an intervention that mobilized sex workers to lead an HIV prevention response that addresses violence in their daily lives. Methods: This study draws on ethnographic research and project monitoring data from a community led structural intervention in Mysore, India, implemented by Ashodaya Samithi. Qualitative and quantitative data were used to characterize baseline conditions, community responses and subsequent outcomes related to violence. Results: In 2004, the incidence of reported violence by sex workers was extremely high (> 8 incidents per sex worker, per year) but decreased by 84 per cent over 5 years. Violence by police and antisocial elements, initially most common, decreased substantially after a safe space was established for sex workers to meet and crisis management and advocacy were initiated with different stakeholders. Violence by clients, decreased after working with lodge owners to improve safety. However, initial increases in intimate partner violence were reported, and may be explained by two factors: (i) increased willingness to report such incidents; and (ii) increased violence as a reaction to sex workers' growing empowerment. Trafficking was addressed through the establishment of a self-regulatory board (SRB). The community's progressive response to violence was enabled by advancing community mobilization, ensuring community ownership of the intervention, and shifting structural vulnerabilities, whereby sex workers increasingly engaged key actors in support of a more enabling environment. Interpretation & conclusions: Ashodaya's community-led response to violence at multiple levels proved highly synergistic and effective in reducing structural violence. [ABSTRACT FROM AUTHOR]
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- 2012
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21. Immunogenicity of Adjuvanted Psoralen-Inactivated SARS-CoV-2 Vaccines and SARS-CoV-2 Spike Protein DNA Vaccines in BALB/c Mice.
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Sundaram AK, Ewing D, Liang Z, Jani V, Cheng Y, Sun P, Raviprakash K, Wu SJ, Petrovsky N, Defang G, Williams M, and Porter KR
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The development of a safe and effective vaccine to protect against COVID-19 is a global priority due to the current high SARS-CoV-2 infection rate. Currently, there are over 160 SARS-CoV-2 vaccine candidates at the clinical or pre-clinical stages of development. Of these, there are only three whole-virus vaccine candidates produced using β-propiolactone or formalin inactivation. Here, we prepared a whole-virus SARS-CoV-2 vaccine (SARS-CoV-2 PsIV) using a novel psoralen inactivation method and evaluated its immunogenicity in mice using two different adjuvants, alum and Advax-2. We compared the immunogenicity of SARS-CoV-2 PsIV against SARS-CoV-2 DNA vaccines expressing either full-length or truncated spike proteins. We also compared the psoralen-inactivated vaccine against a DNA prime, psoralen-inactivated vaccine boost regimen. After two doses, the psoralen-inactivated vaccine, when administered with alum or Advax-2 adjuvants, generated a dose-dependent neutralizing antibody responses in mice. Overall, the pattern of cytokine ELISPOT responses to antigen-stimulation observed in this study indicates that SARS-CoV-2 PsIV with the alum adjuvant promotes a Th2-type response, while SARS-CoV-2 PsIV with the Advax-2 adjuvant promotes a Th1-type response.
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- 2021
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22. Comparison of purified psoralen-inactivated and formalin-inactivated dengue vaccines in mice and nonhuman primates.
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Sundaram AK, Ewing D, Blevins M, Liang Z, Sink S, Lassan J, Raviprakash K, Defang G, Williams M, Porter KR, and Sanders JW
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- Animals, Antibodies, Neutralizing blood, Antibodies, Viral blood, Mice, Primates, Vaccines, Inactivated immunology, Dengue prevention & control, Dengue Vaccines immunology, Ficusin, Formaldehyde, Immunogenicity, Vaccine
- Abstract
Dengue fever, caused by dengue viruses (DENV 1-4) is a leading cause of illness and death in the tropics and subtropics. Therefore, an effective vaccine is urgently needed. Currently, the only available licensed dengue vaccine is a chimeric live attenuated vaccine that shows varying efficacy depending on serotype, age and baseline DENV serostatus. Accordingly, a dengue vaccine that is effective in seronegative adults, children of all ages and in immunocompromised individuals is still needed. We are currently researching the use of psoralen to develop an inactivated tetravalent dengue vaccine. Unlike traditional formalin inactivation, psoralen inactivates pathogens at the nucleic acid level, potentially preserving envelope protein epitopes important for protective anti-dengue immune responses. We prepared highly purified monovalent vaccine lots of formalin- and psoralen-inactivated DENV 1-4, using Capto DeVirS and Capto Core 700 resin based column chromatography. Tetravalent psoralen-inactivated vaccines (PsIV) and formalin-inactivated vaccines (FIV) were prepared by combining the four monovalent vaccines. Mice were immunized with either a low or high dose of PsIV or FIV to evaluate the immunogenicity of monovalent as well as tetravalent formulations of each inactivation method. In general, the monovalent and tetravalent PsIVs elicited equivalent or higher titers of neutralizing antibodies to DENV than the FIV dengue vaccines and this response was dose dependent. The immunogenicity of tetravalent dengue PsIVs and FIVs were also evaluated in nonhuman primates (NHPs). Consistent with what was observed in mice, significantly higher neutralizing antibody titers for each dengue serotype were observed in the NHPs vaccinated with the tetravalent dengue PsIV compared to those vaccinated with the tetravalent dengue FIV, indicative of the importance of envelope protein epitope preservation during psoralen inactivation of DENV., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Kevin Porter holds a patent on “Psoralen-inactivated viral vaccine and method of preparation”. Patent No.: US 9005633B2]., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2020
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23. Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial.
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Beigel JH, Aga E, Elie-Turenne MC, Cho J, Tebas P, Clark CL, Metcalf JP, Ozment C, Raviprakash K, Beeler J, Holley HP Jr, Warner S, Chorley C, Lane HC, Hughes MD, and Davey RT Jr
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- Adolescent, Adult, Aged, Child, Double-Blind Method, Female, Humans, Influenza, Human blood, Influenza, Human virology, Male, Middle Aged, Prospective Studies, Severity of Illness Index, Treatment Outcome, Young Adult, Antibodies, Viral therapeutic use, Immunization, Passive methods, Influenza A virus, Influenza, Human therapy, Plasma immunology
- Abstract
Background: Infection with influenza virus causes substantial morbidity and mortality globally, although antiviral treatments are available. Previous studies have suggested that anti-influenza immune plasma could be beneficial as treatment, but they were not designed as randomised, blinded, placebo-controlled trials. Therefore, we aimed to prospectively evaluate the clinical efficacy of high-titre immune plasma compared with standard low-titre plasma to improve outcomes in patients with severe influenza A infection., Methods: We did this randomised, double-blind, phase 3 trial at 41 US medical centres to assess the efficacy of high-titre anti-influenza plasma (haemagglutination inhibition antibody titre ≥1:80) compared with low-titre plasma (≤1:10). Children and adults with PCR-confirmed influenza A infection, a National Early Warning score of 3 or greater, and onset of illness within 6 days before randomisation were eligible. Patients were randomly assigned (2:1) using an interactive web response system to receive either two units (or paediatric equivalent) of high-titre plasma (high-titre group) or low-titre plasma (low-titre group), and were followed up for 28 days from randomisation. High-titre and low-titre plasma had the same appearance. Randomisation was stratified by severity (in intensive care unit, not in intensive care but requiring supplemental oxygen, or not in intensive care and not requiring supplemental oxygen) and age (<18 years and ≥18 years). All participants, site staff, and the study team were masked to treatment allocation until after the final database lock. The primary endpoint was clinical status assessed by a six-point ordinal scale on day 7 (death, in intensive care, hospitalised but requiring supplemental oxygen, hospitalised not requiring supplemental oxygen, discharged but unable to resume normal activities, and discharged with full resumption of normal activities) analysed in a proportional odds model (an odds ratio [OR] >1 indicates improvement in clinical status across all categories for the high-titre vs the low-titre group). The primary analysis was done in the intention-to-treat population, excluding two participants who did not receive plasma. This trial is registered with ClinicalTrials.gov, NCT02572817., Findings: Participants were recruited between Jan 26, 2016, and April 19, 2018. Of 200 participants enrolled (177 adults and 23 children), 140 met the criteria for randomisation and were assigned to the high-titre group (n=92) or to the control low-titre group (n=48). One participant from each group did not receive plasma. At baseline, 60 (43%) of 138 participants were in intensive care and 55 (71%) of 78 participants who were not in intensive care required oxygen. 93% of planned plasma infusions were completed. The study was terminated in July, 2018, when independent efficacy analysis showed low conditional power to detect an effect of high-titre plasma even if full accrual (150 participants) was achieved. The proportional OR for improved clinical status on day 7 was 1·22 (95% CI 0·65-2·29, p=0·54). 47 (34%) of 138 participants experienced 88 serious adverse events: 32 (35%) with 60 events in the high-titre group and 15 (32%) with 28 events in the low-titre group. The most common serious adverse events were acute respiratory distress syndrome (ARDS; four [4%] vs two [4%]), allergic transfusion reactions (two [2%] vs two [4%]), and respiratory distress (three [3%] vs none). 65 (47%) participants experienced 183 adverse events: 42 (46%) with 126 events in the high-titre group and 23 (49%) with 57 events in the low-titre group. The most common adverse events were anaemia (four [3%] vs two [4%]) and ARDS (four [3%] vs three [5%]). Ten patients died during the study (six [7%] in the high-titre group vs four [9%] in the low-titre group, p=0·73). The most common cause of death was worsening of acute respiratory distress syndrome (two [2%] vs two [4%] patients)., Interpretation: High-titre anti-influenza plasma conferred no significant benefit over non-immune plasma. Although our study did not have the precision to rule out a small, clinically relevant effect, the benefit is insufficient to justify the use of immune plasma for treating patients with severe influenza A., Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD, USA)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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24. Nosocomial outbreak of influenza A H3N2 in an inpatient oncology unit related to health care workers presenting to work while ill.
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Wilson KE, Wood SM, Schaecher KE, Cromwell KB, Godich J, Knapp MH, Sklar MJ, Ewing D, Raviprakash K, Defang G, and Whitman TJ
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- Cross Infection transmission, Cross Infection virology, Female, Hospital Departments, Humans, Infection Control methods, Influenza, Human transmission, Influenza, Human virology, Inpatients, Male, Neoplasms complications, Cross Infection epidemiology, Disease Outbreaks, Health Personnel, Infectious Disease Transmission, Professional-to-Patient, Influenza A Virus, H3N2 Subtype isolation & purification, Influenza, Human epidemiology
- Abstract
Objective: To describe an outbreak of influenza A in an oncology unit, highlighting infection control methods implemented, and examining reasons health care workers (HCWs) present to work with influenza-like illness (ILI)., Methods: Confirmed cases were defined by the presence of ILI and a positive nasopharyngeal polymerase chain reaction swab for influenza A H3. Probable cases were defined as exposed HCWs with ILI who were unavailable for polymerase chain reaction testing. Infection prevention measures included closing the ward for new admissions, oseltamivir prophylaxis for all exposed groups, and dismissal from work of HCWs with ILI until resolution of symptoms. An anonymous survey of the cases in our HCWs was conducted to better elucidate reasons behind presenteeism., Results: Over the course of 8 days (November 16, 2017, to November 22, 2017), influenza was diagnosed in 7 of 10 inpatients on the oncology ward, 16 HCWs (14 confirmed, 2 probable), and 2 visitors. The suspected index case was an HCW. Of the surveyed HCWs, 64% presented to work despite feeling ill (ie, presenteeism). The most common reason was "sense of duty as a health care worker.", Conclusions: This nosocomial outbreak of influenza highlights the challenges of protecting inpatients from viral respiratory tract infections. HCWs and patient visitors with ILI should avoid work or visiting until resolution of peak respiratory symptoms and adhere to strict respiratory etiquette., (Copyright © 2018 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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25. Influence of sample collection tube method, anticoagulant-containing plasma versus serum, on influenza virus hemagglutination inhibition titer and microneutralization titer serological assays.
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Morrison BJ, Martin NJ, Rehman T, Ewing D, Dewar RL, Metcalf J, Sun P, Beigel J, Luke TC, and Raviprakash K
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- Antibodies, Viral, Anticoagulants, Guidelines as Topic, Humans, Influenza Vaccines, Influenza, Human blood, Neutralization Tests, Blood Specimen Collection methods, Hemagglutination immunology, Hemagglutination Inhibition Tests, Influenza A Virus, H1N1 Subtype immunology, Influenza A Virus, H3N2 Subtype immunology, Influenza, Human immunology
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Background: The hemagglutination-inhibition (HAI) assay is a critical component for measurement of immunogenicity in influenza vaccine development. It is unknown if the results can be influenced by sample type and anticoagulants. The purpose of this study was to evaluate the influence of different sample collection methods, in particular different anticoagulants, and choice of plasma or serum, on influenza virus serological assays., Methods: Blood samples from thirty donors previously immunized against influenza viruses were collected using six different types of blood collection tubes, two of which collect serum and four of which contain various anticoagulants for collecting plasma. Serum: (1) serum separator tubes (SST); and (2) Plus Plastic serum "red-top serum" tubes. Plasma: (3) spray-coated K2 ethylenediaminetetraacetic acid (EDTA) tubes: (4) Sodium Heparin tubes; (5) Citrate tubes with 3.2% sodium citrate solution; and (6) Glass Blood Collection tubes with acid citrate dextrose. Samples were tested against three different influenza viruses (A/California/07/2009 (H1N1pdm09), A/Texas/50/2012 (H3N2), and B/Massachusetts/2/2012) for hemagglutination inhibition titer and virus neutralization titer via a microneutralization (MN) assay, and data compared to that obtained for standard serum sample collected in SST., Results: HAI and MN titers against type A viruses were within two dilutions compared to SST collection method over 96% of the time irrespective of sample type or anticoagulant. However, HAI titers for type B virus were more variable across different collection methods. EDTA plasma samples were greater than two dilutions higher than SST serum samples 70% (21 of 30 samples) of the time. In contrast, MN titers were within two dilutions over 96% of the time, with the highest deviation noted in acid citrate dextrose plasma samples (3 of 30 samples tested, 10%)., Conclusions: These data provide useful guidelines for sample collection and serology testing when screening: (i) influenza vaccine immunogenicity antibody response; (ii) antibody responses to newly emerging viral strains; and (iii) clinical samples for anti-influenza antibody activity.
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- 2018
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26. Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study.
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Beigel JH, Voell J, Kumar P, Raviprakash K, Wu H, Jiao JA, Sullivan E, Luke T, and Davey RT Jr
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- Adult, Animals, Animals, Genetically Modified, Cattle, Double-Blind Method, Drug-Related Side Effects and Adverse Reactions epidemiology, Drug-Related Side Effects and Adverse Reactions pathology, Female, Follow-Up Studies, Healthy Volunteers, Humans, Immunoglobulin G administration & dosage, Immunoglobulin G adverse effects, Infusions, Intravenous, Male, Middle Aged, National Institutes of Health (U.S.), Placebos administration & dosage, United States, Young Adult, Antibodies, Viral administration & dosage, Antibodies, Viral adverse effects, Immunization, Passive adverse effects, Immunization, Passive methods, Middle East Respiratory Syndrome Coronavirus immunology
- Abstract
Background: Middle East respiratory syndrome (MERS) is a severe respiratory illness with an overall mortality of 35%. There is no licensed or proven treatment. Passive immunotherapy approaches are being developed to prevent and treat several human medical conditions where alternative therapeutic options are absent. We report the safety of a fully human polyclonal IgG antibody (SAB-301) produced from the hyperimmune plasma of transchromosomic cattle immunised with a MERS coronavirus vaccine., Methods: We did a phase 1 double-blind, placebo-controlled, single-dose escalation trial at the National Institutes of Health Clinical Center. We recruited healthy participants aged 18-60 years who had normal laboratory parameters at enrolment, a body-mass index of 19-32 kg/m
2 , and a creatinine clearance of 70 mL/min or more, and who did not have any chronic medical problems that required daily oral medications, a positive rheumatoid factor (≥15 IU/mL), IgA deficiency (<7 mg/dL), or history of allergy to intravenous immunoglobulin or human blood products. Participants were randomly assigned by a computer-generated table, made by a masked pharmacist, to one of six cohorts (containing between three and ten participants each). Cohorts 1 and 2 had three participants, randomly assigned 2:1 to receive active drug SAB-301 versus normal saline placebo; cohorts 3 and 4 had six participants randomised 2:1; and cohorts 5 and 6 had ten participants, randomised 4:1. Participants received 1 mg/kg, 2·5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, or 50 mg/kg of SAB-301, or equivalent volume placebo (saline control), on day 0, and were followed up by clinical, laboratory, and pharmacokinetic assessments on days 1, 3, 7, 21, 42, and 90. The primary outcome was safety, and immunogenicity was a secondary outcome. We analysed the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02788188., Findings: Between June 2, 2016, and Jan 4, 2017, we screened 43 participants, of whom 38 were eligible and randomly assigned to receive SAB-301 (n=28) or placebo (n=10). 97 adverse events were reported: 64 adverse events occurred in 23 (82%) of 28 participants receiving SAB-301 (mean 2·3 adverse events per participant). 33 adverse events occurred in all ten participants receiving placebo (mean 3·3 adverse events per participant). The most common adverse events were headache (n=6 [21%] in participants who received SAB-301 and n=2 [20%] in those receiving placebo), albuminuria (n=5 [18%] vs n=2 [20%]), myalgia (n=3 [11%] vs n=1 [10%]), increased creatine kinase (n=3 [11%] vs 1 [10%]), and common cold (n=3 [11%] vs n=2 [20%]). There was one serious adverse event (hospital admission for suicide attempt) in one participant who received 50 mg/kg of SAB-301. The area under the concentration-time curve (AUC) in the 50 mg/kg dose (27 498 μg × days per mL) is comparable to the AUC that was associated with efficacy in a preclinical model., Interpretation: Single infusions of SAB-301 up to 50 mg/kg appear to be safe and well tolerated in healthy participants. Human immunoglobulin derived from transchromosomic cattle could offer a new platform technology to produce fully human polyclonal IgG antibodies for other medical conditions., Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Biomedical Advanced Research and Development Authority., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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27. Safety and Immunogenicity of a Tetravalent Dengue DNA Vaccine Administered with a Cationic Lipid-Based Adjuvant in a Phase 1 Clinical Trial.
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Danko JR, Kochel T, Teneza-Mora N, Luke TC, Raviprakash K, Sun P, Simmons M, Moon JE, De La Barrera R, Martinez LJ, Thomas SJ, Kenney RT, Smith L, and Porter KR
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- Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic chemistry, Adult, Dengue immunology, Dengue virology, Dengue Vaccines adverse effects, Fatigue etiology, Fatigue physiopathology, Female, Headache etiology, Headache physiopathology, Humans, Immunization Schedule, Immunogenicity, Vaccine, Injections, Intramuscular, Interferon-gamma biosynthesis, Interferon-gamma immunology, Male, Myalgia etiology, Myalgia physiopathology, Patient Safety, Phosphatidylethanolamines administration & dosage, Phosphatidylethanolamines chemistry, Vaccination, Vaccines, DNA adverse effects, Antibodies, Neutralizing biosynthesis, Antibodies, Viral biosynthesis, Dengue prevention & control, Dengue Vaccines administration & dosage, Dengue Virus immunology, Immunity, Cellular drug effects, Vaccines, DNA administration & dosage
- Abstract
We conducted an open label, dose escalation Phase 1 clinical trial of a tetravalent dengue DNA vaccine (TVDV) formulated in Vaxfectin
® to assess safety and immunogenicity. A total of 40 dengue- and flavivirus-naive volunteers received either low-dose (1 mg) TVDV alone ( N = 10, group 1), low-dose TVDV (1 mg) formulated in Vaxfectin ( N = 10, group 2), or high-dose TVDV (2 mg, group 3) formulated in Vaxfectin® ( N = 20). Subjects were immunized intramuscularly with three doses on a 0-, 30-, 90-day schedule and monitored. Blood samples were obtained after each immunization and various time points thereafter to assess anti-dengue antibody and interferon gamma (IFNγ) T-cell immune responses. The most common adverse events (AEs) across all groups included mild to moderate pain and tenderness at the injection site, which typically resolved within 7 days. Common solicited signs and symptoms included fatigue (42.5%), headache (45%), and myalgias (47.5%). There were no serious AEs related to the vaccine or study procedures. No anti-dengue antibody responses were detected in group 1 subjects who received all three immunizations. There were minimal enzyme-linked immunosorbent assay and neutralizing antibody responses among groups 2 and 3 subjects who completed the immunization schedule. By contrast, IFNγ T-cell responses, regardless of serotype specificity, occurred in 70%, 50%, and 79% of subjects in groups 1, 2, and 3, respectively. The largest IFNγ T-cell responses were among group 3 subjects. We conclude that TVDV was safe and well-tolerated and elicited predominately anti-dengue T-cell IFNγ responses in a dose-related fashion.- Published
- 2018
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28. Antibody-dependent NK cell degranulation as a marker for assessing antibody-dependent cytotoxicity against pandemic 2009 influenza A(H1N1) infection in human plasma and influenza-vaccinated transchromosomic bovine intravenous immunoglobulin therapy.
- Author
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Morrison BJ, Roman JA, Luke TC, Nagabhushana N, Raviprakash K, Williams M, and Sun P
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Viral blood, Biomarkers blood, Cattle, Cell Degranulation, Cell Line, Hemagglutination Inhibition Tests, Hemagglutinin Glycoproteins, Influenza Virus immunology, Humans, Immunoglobulins, Intravenous administration & dosage, Influenza Vaccines administration & dosage, Influenza Vaccines immunology, Influenza, Human blood, Influenza, Human virology, Lymphocyte Activation, Lysosomal-Associated Membrane Protein 1 immunology, Antibody-Dependent Cell Cytotoxicity, Immunoassay, Immunoglobulins, Intravenous therapeutic use, Influenza A Virus, H1N1 Subtype immunology, Influenza, Human immunology, Influenza, Human therapy, Killer Cells, Natural immunology
- Abstract
This study describes an antibody-dependent NK cell degranulation assay, as a biomarker to assess antibody-dependent cellular cytotoxicity (ADCC) response in influenza plasma and for antibody therapies against influenza infection. The concentration of neutralizing antibodies (NAbs) against the hemagglutinin receptor of influenza viruses is a current determinant in protection against infection, particularly following receipt of the seasonal influenza vaccine. However, this is a limited assessment of protection, because: (i) NAb titers that incur full protection vary; and (ii) NAb titers do not account for the entire breadth of antibody responses against viral infection. Previous reports have indicated that antibodies that prime ADCC play a vital role in controlling influenza infections, and thus should be quantified for assessing protection against influenza. This report demonstrates a non-radioactive assay that assesses NK cell activation as a marker of ADCC, in which NK cells interact with opsonized viral antigen expressed on the surface of infected Raji target cells resulting in effector cell degranulation (surrogate CD107a expression). A positive correlation was determined between HAI titers and sustained NK cell activation, although NK cell activation was seen in plasma samples with HAI titers below 40 and varied amongst samples with high HAI titers. Furthermore, sustained NK cell degranulation was determined for influenza-vaccinated transchromosomic bovine intravenous immunoglobulin, indicating the potential utility of this therapy for influenza treatment. We conclude that this assay is reproducible and relevant., (Published by Elsevier B.V.)
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- 2017
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29. Antibody Preparations from Human Transchromosomic Cows Exhibit Prophylactic and Therapeutic Efficacy against Venezuelan Equine Encephalitis Virus.
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Gardner CL, Sun C, Luke T, Raviprakash K, Wu H, Jiao JA, Sullivan E, Reed DS, Ryman KD, and Klimstra WB
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- Animals, Antibodies, Viral isolation & purification, Cattle, Disease Models, Animal, Humans, Mice, Treatment Outcome, Animals, Genetically Modified, Antibodies, Viral administration & dosage, Encephalitis Virus, Venezuelan Equine immunology, Encephalomyelitis, Venezuelan Equine prevention & control, Encephalomyelitis, Venezuelan Equine therapy, Immunization, Passive
- Abstract
Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne RNA virus that causes low mortality but high morbidity rates in humans. In addition to natural outbreaks, there is the potential for exposure to VEEV via aerosolized virus particles. There are currently no FDA-licensed vaccines or antiviral therapies for VEEV. Passive immunotherapy is an approved method used to protect individuals against several pathogens and toxins. Human polyclonal antibodies (PAbs) are ideal, but this is dependent upon serum from convalescent human donors, which is in limited supply. Non-human-derived PAbs can have serious immunoreactivity complications, and when "humanized," these antibodies may exhibit reduced neutralization efficiency. To address these issues, transchromosomic (Tc) bovines have been created, which can produce potent neutralizing human antibodies in response to hyperimmunization. In these studies, we have immunized these bovines with different VEEV immunogens and evaluated the protective efficacy of purified preparations of the resultant human polyclonal antisera against low- and high-dose VEEV challenges. These studies demonstrate that prophylactic or therapeutic administration of the polyclonal antibody preparations (TcPAbs) can protect mice against lethal subcutaneous or aerosol challenge with VEEV. Furthermore, significant protection against unrelated coinfecting viral pathogens can be conferred by combining individual virus-specific TcPAb preparations. IMPORTANCE With the globalization and spread or potential aerosol release of emerging infectious diseases, it will be critical to develop platforms that are able to produce therapeutics in a short time frame. By using a transchromosomic (Tc) bovine platform, it is theoretically possible to produce antigen-specific highly neutralizing therapeutic polyclonal human antibody (TcPAb) preparations in 6 months or less. In this study, we demonstrate that Tc bovine-derived Venezuelan equine encephalitis virus (VEEV)-specific TcPAbs are highly effective against VEEV infection that mimics not only the natural route of infection but also infection via aerosol exposure. Additionally, we show that combinatorial TcPAb preparations can be used to treat coinfections with divergent pathogens, demonstrating that the Tc bovine platform could be beneficial in areas where multiple infectious diseases occur contemporaneously or in the case of multipathogen release., (Copyright © 2017 American Society for Microbiology.)
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- 2017
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30. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study.
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Beigel JH, Tebas P, Elie-Turenne MC, Bajwa E, Bell TE, Cairns CB, Shoham S, Deville JG, Feucht E, Feinberg J, Luke T, Raviprakash K, Danko J, O'Neil D, Metcalf JA, King K, Burgess TH, Aga E, Lane HC, Hughes MD, and Davey RT
- Subjects
- Adult, Aged, Case-Control Studies, Female, Humans, Kaplan-Meier Estimate, Length of Stay, Male, Middle Aged, Respiration, Artificial statistics & numerical data, Treatment Outcome, Blood Component Transfusion, Influenza, Human therapy, Plasma
- Abstract
Background: Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of severe influenza., Methods: In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ≤20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480., Findings: Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96-3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 [95% CI 0·02-1·65], p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days [IQR 4-16] vs 11 days [5-25], p=0·13) and days on mechanical ventilation (median 0 days [IQR 0-6] vs 3 days [0-14], p=0·14). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine [20%] of 46 vs 20 [38%] of 52, p=0·041), the most frequent of which were acute respiratory distress syndrome (one [2%] vs two [4%] patients) and stroke (one [2%] vs two [4%] patients)., Interpretation: Although there was no significant effect of plasma treatment on the primary endpoint, the treatment seemed safe and well tolerated. A phase 3 randomised trial is now underway to further assess this intervention., Funding: National Institute of Allergy and Infectious Diseases, US National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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31. DNA Vaccine Delivery and Improved Immunogenicity.
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Porter KR and Raviprakash K
- Subjects
- Administration, Mucosal, Animals, Humans, Skin Absorption, Vaccines, DNA administration & dosage, Immunogenicity, Vaccine, Vaccination, Vaccines, DNA immunology
- Abstract
The promise of DNA vaccines is as compelling today as it was more than a decade ago. Ease of manufacture, stability at ambient temperatures without the need for a cold chain and its ability to mimic natural infections and elicit appropriate immune responses makes this vaccine platform extremely attractive. Although, human clinical trials of DNA vaccines have yielded less than optimal results, the approval and licensing of a few veterinary vaccines is testimony to the proof-of-concept and the hope that licensed DNA vaccines for human use may not be too far away. Delivery and targeting of immunologically relevant cells appears to be the major hurdle in maximizing the immunogenicity of DNA vaccines. Several different approaches that are currently pursued in achieving this objective are discussed.
- Published
- 2017
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32. Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia.
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Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al-Omari A, Al-Hameed F, Hayden FG, Fowler R, Bouchama A, Shindo N, Al-Khairy K, Carson G, Taha Y, Sadat M, and Alahmadi M
- Subjects
- Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Coronavirus Infections immunology, Enzyme-Linked Immunosorbent Assay, Health Personnel, Humans, Immunoglobulin G immunology, Middle East Respiratory Syndrome Coronavirus genetics, Neutralization Tests, RNA, Viral, Reverse Transcriptase Polymerase Chain Reaction, Saudi Arabia, Coronavirus Infections therapy, Coronavirus Infections virology, Immunotherapy methods, Middle East Respiratory Syndrome Coronavirus immunology, Plasma immunology
- Abstract
We explored the feasibility of collecting convalescent plasma for passive immunotherapy of Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using ELISA to screen serum samples from 443 potential plasma donors: 196 patients with suspected or laboratory-confirmed MERS-CoV infection, 230 healthcare workers, and 17 household contacts exposed to MERS-CoV. ELISA-reactive samples were further tested by indirect fluorescent antibody and microneutralization assays. Of the 443 tested samples, 12 (2.7%) had a reactive ELISA result, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. Undertaking clinical trials of convalescent plasma for passive immunotherapy of MERS-CoV infection may be feasible, but such trials would be challenging because of the small pool of potential donors with sufficiently high antibody titers. Alternative strategies to identify convalescent plasma donors with adequate antibody titers should be explored, including the sampling of serum from patients with more severe disease and sampling at earlier points during illness.
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- 2016
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33. Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo.
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Luke T, Wu H, Zhao J, Channappanavar R, Coleman CM, Jiao JA, Matsushita H, Liu Y, Postnikova EN, Ork BL, Glenn G, Flyer D, Defang G, Raviprakash K, Kochel T, Wang J, Nie W, Smith G, Hensley LE, Olinger GG, Kuhn JH, Holbrook MR, Johnson RF, Perlman S, Sullivan E, and Frieman MB
- Subjects
- Animals, Antibodies, Neutralizing immunology, Antibody-Dependent Enhancement, Cattle, Dipeptidyl Peptidase 4 metabolism, Enzyme-Linked Immunosorbent Assay, Humans, Mice, Inbred BALB C, Middle East Respiratory Syndrome Coronavirus genetics, Middle East Respiratory Syndrome Coronavirus physiology, Neutralization Tests, RNA, Messenger genetics, RNA, Messenger metabolism, Transduction, Genetic, Vaccination, Virus Replication, Chromosomes, Mammalian genetics, Immunoglobulin G immunology, Middle East Respiratory Syndrome Coronavirus immunology
- Abstract
As of 13 November 2015, 1618 laboratory-confirmed human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, including 579 deaths, had been reported to the World Health Organization. No specific preventive or therapeutic agent of proven value against MERS-CoV is currently available. Public Health England and the International Severe Acute Respiratory and Emerging Infection Consortium identified passive immunotherapy with neutralizing antibodies as a treatment approach that warrants priority study. Two experimental MERS-CoV vaccines were used to vaccinate two groups of transchromosomic (Tc) bovines that were genetically modified to produce large quantities of fully human polyclonal immunoglobulin G (IgG) antibodies. Vaccination with a clade A γ-irradiated whole killed virion vaccine (Jordan strain) or a clade B spike protein nanoparticle vaccine (Al-Hasa strain) resulted in Tc bovine sera with high enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody titers in vitro. Two purified Tc bovine human IgG immunoglobulins (Tc hIgG), SAB-300 (produced after Jordan strain vaccination) and SAB-301 (produced after Al-Hasa strain vaccination), also had high ELISA and neutralizing antibody titers without antibody-dependent enhancement in vitro. SAB-301 was selected for in vivo and preclinical studies. Administration of single doses of SAB-301 12 hours before or 24 and 48 hours after MERS-CoV infection (Erasmus Medical Center 2012 strain) of Ad5-hDPP4 receptor-transduced mice rapidly resulted in viral lung titers near or below the limit of detection. Tc bovines, combined with the ability to quickly produce Tc hIgG and develop in vitro assays and animal model(s), potentially offer a platform to rapidly produce a therapeutic to prevent and/or treat MERS-CoV infection and/or other emerging infectious diseases., (Copyright © 2016, American Association for the Advancement of Science.)
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- 2016
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34. Nucleic acid (DNA) immunization as a platform for dengue vaccine development.
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Porter KR and Raviprakash K
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Viral blood, Clinical Trials, Phase I as Topic, Dengue epidemiology, Dengue Vaccines genetics, Dengue Vaccines isolation & purification, Drug Evaluation, Preclinical, Humans, Primates, Vaccines, DNA genetics, Vaccines, DNA isolation & purification, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, Vaccines, Synthetic isolation & purification, Dengue prevention & control, Dengue Vaccines administration & dosage, Dengue Vaccines immunology, Vaccines, DNA administration & dosage, Vaccines, DNA immunology
- Abstract
Since the early 1990s, DNA immunization has been used as a platform for developing a tetravalent dengue vaccine in response to the high priority need for protecting military personnel deployed to dengue endemic regions of the world. Several approaches have been explored ranging from naked DNA immunization to the use of live virus vectors to deliver the targeted genes for expression. Pre-clinical animal studies were largely successful in generating anti-dengue cellular and humoral immune responses that were protective either completely or partially against challenge with live dengue virus. However, Phase 1 clinical evaluation of a prototype monovalent dengue 1 DNA vaccine expressing prM and E genes revealed anti-dengue T cell IFNγ responses, but poor neutralizing antibody responses. These less than optimal results are thought to be due to poor uptake and expression of the DNA vaccine plasmids. Because DNA immunization as a vaccine platform has the advantages of ease of manufacture, flexible genetic manipulation and enhanced stability, efforts continue to improve the immunogenicity of these vaccines using a variety of methods., (Published by Elsevier Ltd.)
- Published
- 2015
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35. Self-administration of intranasal influenza vaccine: Immunogenicity and volunteer acceptance.
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Burgess TH, Murray CK, Bavaro MF, Landrum ML, O'Bryan TA, Rosas JG, Cammarata SM, Martin NJ, Ewing D, Raviprakash K, Mor D, Zell ER, Wilkins KJ, and Millar EV
- Subjects
- Administration, Intranasal, Adult, Antibodies, Viral blood, Female, Healthy Volunteers, Hemagglutination Inhibition Tests, Hemagglutinin Glycoproteins, Influenza Virus immunology, Humans, Male, Vaccines, Attenuated administration & dosage, Vaccines, Attenuated immunology, Influenza Vaccines administration & dosage, Influenza Vaccines immunology, Patient Acceptance of Health Care, Self Administration psychology
- Abstract
Background: In outbreak settings, mass vaccination strategies could maximize health protection of military personnel. Self-administration of live attenuated influenza vaccine (LAIV) may be a means to vaccinate large numbers of people and achieve deployment readiness while sparing the use of human resources., Methods: A phase IV, open-label, randomized controlled trial evaluating the immunogenicity and acceptance of self-administered (SA) LAIV was conducted from 2012 to 2014. SA subjects were randomized to either individual self-administration or self-administration in a group setting. Control randomized subjects received healthcare worker-administered (HCWA) LAIV. Anti-hemagglutinin (HAI) antibody concentrations were measured pre- and post-vaccination. The primary endpoint was immunogenicity non-inferiority between SA and HCWA groups. Subjects were surveyed on preferred administration method., Results: A total of 1077 subjects consented and were randomized (529 SA, 548 HCWA). Subject characteristics were very similar between groups, though SA subjects were younger, more likely to be white and on active duty. The per-protocol analysis included 1024 subjects (501 SA, 523 HCWA). Post-vaccination geometric mean titers by vaccine strain and by study group (HCWA vs. SA) were: A/H1N1 (45.8 vs. 48.7, respectively; p=0.43), A/H3N2 (45.5 vs. 46.4; p=0.80), B/Yamagata (17.2 vs. 17.8; p=0.55). Seroresponses to A components were high (∼67%), while seroresponses to B components were lower (∼25%). Seroresponse did not differ by administration method. Baseline preference for administration method was similar between groups, with the majority in each group expressing no preference. At follow-up, the majority (64%) of SA subjects preferred SA vaccine., Conclusions: LAIV immunogenicity was similar for HCWA and SA vaccines. SA was well-tolerated and preferred to HCWA among those who performed SA., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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36. Dengue serosurvey in Sint Eustatius.
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Leslie T, Martin NJ, Jack-Roosberg C, Odongo G, Beausoleil E, Tuck J, Raviprakash K, and Kochel TJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Caribbean Region, Child, Dengue blood, Dengue Virus genetics, Dengue Virus immunology, Female, Humans, Male, Middle Aged, Serogroup, Antibodies, Viral blood, Dengue epidemiology
- Abstract
Four distinct serotypes of dengue viruses (DENV) are the cause of re-emerging dengue fever (DF) and dengue hemorrhagic fever (DHF). Dengue circulation in the Caribbean has gone from none or single serotype to multiple serotypes co-circulating with reports of continuing cycles of progressively more severe disease in the region. Few studies have investigated dengue on Sint Eustatius. Blood samples were collected to determine the prevalence of antibodies against dengue in the Sint Eustatius population. Greater than 90% of the serum samples (184 of 204) were positive for anti-flavivirus antibodies by enzyme linked immunosorbance assay (ELISA). Plaque reduction neutralization test (PRNT), specific for dengue viruses, showed that 171 of these 184 flavivirus antibody positive sera had a neutralization titer against one or more DENV serotypes. A majority of the sera (62%) had neutralizing antibody to all four dengue serotypes. Only 26 PRNT positive sera (15%) had monotypic dengue virus neutralizing antibody, most of which (20 of 26) were against DENV2. Evidence of infection with all four serotypes was observed across all age groups except in the youngest age group (10-19 years) which contained only DENV2 positive individuals. In a multiple logistic regression model, only the length of residence on the island was a predictor of a positive dengue PRNT50 result. To our knowledge this is the first dengue serosurveillance study conducted on Sint Eustatius since the 1970s. The lack of antibodies to the DEN1, 3, and 4 in the samples collected from participants under 20 years of age suggests that only DEN2 has circulated on island since the early 1990s. The high prevalence of antibodies against dengue (83.8%) and the observation that the length of time on the island was the strongest predictor of infection suggests dengue is endemic on Sint Eustatius and a public health concern that warrants further investigation.
- Published
- 2014
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37. Full-genome sequence of human betacoronavirus 2c jordan-n3/2012 after serial passage in Mammalian cells.
- Author
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Frey KG, Redden CL, Bishop-Lilly KA, Johnson R, Hensley LE, Raviprakash K, Luke T, Kochel T, Mokashi VP, and Defang GN
- Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is the etiologic agent of a highly lethal pneumonia. Here, we report the full-genome sequence of the Jordan-N3/2012 strain after serial passage in two distinct mammalian cell lines. The genome exhibits noteworthy stability, which may inform the development of vaccines and therapeutics used to treat infection with this virus., (Copyright © 2014 Frey et al.)
- Published
- 2014
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38. Tetravalent DNA vaccine product as a vaccine candidate against dengue.
- Author
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Porter KR, Teneza-Mora N, and Raviprakash K
- Subjects
- Clinical Trials, Phase I as Topic, Humans, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Viral Vaccines administration & dosage, Viral Vaccines genetics, Dengue prevention & control, Vaccines, DNA immunology, Viral Vaccines immunology
- Abstract
Dengue is the most important arbovirus worldwide and is the virus that causes dengue fever and the more severe dengue hemorrhagic fever. There are four serotypes of dengue with each possessing the ability to cause disease. Developing a preventive vaccine is the most efficient and effective way to prevent these diseases, and because immunity to one serotype does not protect against the other serotypes, a vaccine must provide tetravalent protection. We used DNA immunization as a platform to develop a tetravalent vaccine. In this chapter, we describe the laboratory, regulatory, and clinical methodology for evaluating a candidate tetravalent vaccine in a Phase 1 clinical trial.
- Published
- 2014
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39. Dengue virus photo-inactivated in presence of 1,5-iodonaphthylazide (INA) or AMT, a psoralen compound (4'-aminomethyl-trioxsalen) is highly immunogenic in mice.
- Author
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Raviprakash K, Sun P, Raviv Y, Luke T, Martin N, and Kochel T
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Viral blood, Dengue Vaccines administration & dosage, Formaldehyde pharmacology, Light, Mice, Inbred BALB C, T-Lymphocytes immunology, Trioxsalen pharmacology, Vaccines, Inactivated administration & dosage, Vaccines, Inactivated immunology, Azides pharmacology, Dengue Vaccines immunology, Dengue Virus drug effects, Dengue Virus immunology, Disinfectants pharmacology, Trioxsalen analogs & derivatives, Virus Inactivation
- Abstract
Two novel methods of dengue virus inactivation using iodonaphthyl azide (INA) and aminomethyl trioxsalen (AMT) were compared with traditional virus inactivation by formaldehyde. The AMT inactivated dengue-2 virus retained its binding to a panel of 5 monoclonal antibodies specific for dengue-2 envelope protein, whereas inactivation by formaldehyde and INA led to 30-50% decrease in binding. All three inactivated viruses elicited high level virus neutralizing antibodies in vaccinated mice. However, only mice vaccinated with AMT inactivated virus mounted T cell responses similar to live, uninactivated virus.
- Published
- 2013
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40. A dengue DNA vaccine formulated with Vaxfectin® is well tolerated, and elicits strong neutralizing antibody responses to all four dengue serotypes in New Zealand white rabbits.
- Author
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Raviprakash K, Luke T, Doukas J, Danko J, Porter K, Burgess T, and Kochel T
- Subjects
- Adjuvants, Immunologic adverse effects, Animals, Dengue immunology, Dengue Vaccines administration & dosage, Dengue Vaccines adverse effects, Dengue Vaccines genetics, Dengue Virus genetics, Dengue Virus immunology, Female, Injections, Intramuscular, Male, Phosphatidylethanolamines adverse effects, Rabbits, Vaccination methods, Vaccines, DNA administration & dosage, Vaccines, DNA adverse effects, Vaccines, DNA genetics, Adjuvants, Immunologic administration & dosage, Antibodies, Neutralizing blood, Antibodies, Viral blood, Dengue prevention & control, Dengue Vaccines immunology, Phosphatidylethanolamines administration & dosage, Vaccines, DNA immunology
- Abstract
A tetravalent DNA vaccine formulated with Vaxfectin adjuvant was shown to elicit high levels of neutralizing antibody against all four dengue virus serotypes (Porter et al., ( 16) ), warranting further testing in humans. In preparation for a phase 1 clinical testing, the vaccine and the adjuvant were manufactured under current good manufacturing practice guidelines. The formulated vaccine and the adjuvant were tested for safety and/or immunogenicity in New Zealand white rabbits using a repeat dose toxicology study. The formulated vaccine and the adjuvant were found to be well tolerated by the animals. Animals injected with formulated vaccine produced strong neutralizing antibody response to all four dengue serotypes.
- Published
- 2012
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41. Immunogenicity and protective efficacy of a vaxfectin-adjuvanted tetravalent dengue DNA vaccine.
- Author
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Porter KR, Ewing D, Chen L, Wu SJ, Hayes CG, Ferrari M, Teneza-Mora N, and Raviprakash K
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Viral blood, Dengue prevention & control, Dengue Vaccines administration & dosage, Disease Models, Animal, Enzyme-Linked Immunospot Assay, Macaca mulatta, Primates, T-Lymphocytes immunology, Vaccines, DNA administration & dosage, Viremia prevention & control, Adjuvants, Immunologic administration & dosage, Dengue veterinary, Dengue Vaccines immunology, Phosphatidylethanolamines administration & dosage, Primate Diseases prevention & control, Vaccines, DNA immunology
- Abstract
A prototype dengue-1 DNA vaccine was shown to be safe and immunogenic in a previous Phase 1 clinical trial. Anti-dengue-1 neutralizing antibody responses were detectable only in the group of volunteers receiving the high dose of nonadjuvanted vaccine and the antibody titers were low. Vaxfectin(®), a lipid-based adjuvant, enhances the immunogenicity of DNA vaccines. We conducted a nonhuman primate study to evaluate the effect of Vaxfectin(®) on the immunogenicity of a tetravalent dengue DNA vaccine. Animals were immunized on days 0, 28 and 84, with each immunization consisting of 3mg of Vaxfectin(®)-adjuvanted tetravalent dengue DNA vaccine. The use of Vaxfectin(®) resulted in a significant increase in anti-dengue neutralizing antibody responses against dengue-1, -3 and -4. There was little to no effect on T cell responses as measured by interferon gamma ELISPOT assay. Animals immunized with the Vaxfectin(®)-formulated tetravalent DNA vaccine showed significant protection against live dengue-2 virus challenge compared to control animals (0.75 mean days of viremia vs 3.3 days). Animals vaccinated with nonadjuvanted DNA had a mean 2.0 days of viremia. These results support further evaluation of the Vaxfectin(®)-adjuvanted tetravalent dengue DNA vaccine in a Phase 1 clinical trial., (Published by Elsevier Ltd.)
- Published
- 2012
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42. Evaluation of a prototype dengue-1 DNA vaccine in a Phase 1 clinical trial.
- Author
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Beckett CG, Tjaden J, Burgess T, Danko JR, Tamminga C, Simmons M, Wu SJ, Sun P, Kochel T, Raviprakash K, Hayes CG, and Porter KR
- Subjects
- Adolescent, Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, Dengue Vaccines administration & dosage, Humans, Immunization, Secondary methods, Injections, Intramuscular, Middle Aged, Pain chemically induced, Skin Diseases chemically induced, Vaccines, DNA administration & dosage, Young Adult, Dengue prevention & control, Dengue Vaccines adverse effects, Dengue Vaccines immunology, Vaccines, DNA adverse effects, Vaccines, DNA immunology
- Abstract
Candidate dengue DNA vaccine constructs for each dengue serotype were developed by incorporating pre-membrane and envelope genes into a plasmid vector. A Phase 1 clinical trial was performed using the dengue virus serotype-1 (DENV-1) vaccine construct (D1ME(100)). The study was an open-label, dose-escalation, safety and immunogenicity trial involving 22 healthy flavivirus-naïve adults assigned to one of two groups. Each group received three intramuscular injections (0, 1, and 5 months) of either a high dose (5.0mg, n=12) or a low dose (1.0mg, n=10) DNA vaccine using the needle-free Biojector(®) 2000. The most commonly reported solicited signs and symptoms were local mild pain or tenderness (10/22, 45%), local mild swelling (6/22, 27%), muscle pain (6/22, 27%) and fatigue (6/22, 27%). Five subjects (41.6%) in the high dose group and none in the low dose group developed detectable anti-dengue neutralizing antibodies. T-cell IFN gamma responses were detected in 50% (4/8) and 83.3% (10/12) of subjects in the low and high dose groups, respectively. The safety profile of the DENV-1 DNA vaccine is acceptable at both doses administered in the study. These results demonstrate a favorable reactogenicity and safety profile of the first in human evaluation of a DENV-1 DNA vaccine., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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43. Advances in dengue vaccine development.
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Raviprakash K, Defang G, Burgess T, and Porter K
- Subjects
- Animals, Clinical Trials as Topic, Dengue Vaccines administration & dosage, Dengue Virus genetics, Humans, Vaccines, DNA administration & dosage, Vaccines, DNA immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, Dengue immunology, Dengue prevention & control, Dengue Vaccines immunology, Dengue Virus immunology, Tropical Medicine trends, Vaccination
- Abstract
Dengue viruses are the most important arboviruses causing human disease. Expansion of the disease in recent decades to include more geographical areas of the world, an appreciation of the disease burden and market potentials have spurred a flurry of activity in the development of vaccines to combat dengue viruses. Recent progress in this area and some of the obstacles associated with this development are discussed.
- Published
- 2009
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44. A dry-format field-deployable quantitative reverse transcriptase-polymerase chain reaction assay for diagnosis of dengue infections.
- Author
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Wu SJ, Pal S, Ekanayake S, Greenwald D, Lara S, Raviprakash K, Kochel T, Porter K, Hayes C, Nelson W, and Callahan J
- Subjects
- Humans, Sensitivity and Specificity, Viral Load, Dengue diagnosis, RNA, Viral blood, Reverse Transcriptase Polymerase Chain Reaction methods
- Abstract
We have systematically evaluated a dry-format, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay developed by Tetracore Inc. for the Cepheid SmartCycler platform to facilitate rapid diagnosis of dengue virus infections. A panel of related flaviviruses was used to evaluate the clinical specificity of the assay, and it was found to be specific to dengue. Eighty-one clinical samples previously confirmed dengue positive by virus isolation, along with 25 dengue negative control specimens were used to validate this new diagnostic assay. Using these clinical samples, the assay exhibited 98.77% sensitivity and 100% specificity. Over 85% of the clinical specimen exhibited viral loads ranging from 10(3) to 10(7) plaque-forming units per milliliter (PFU/mL). In addition, this dry-format assay is stable at ambient temperatures and requires minimal technical expertise to perform in a small thermocycler platform. These characteristics make it a promising candidate for diagnosis of dengue in mobile laboratories in the field.
- Published
- 2008
45. A tetravalent dengue vaccine based on a complex adenovirus vector provides significant protection in rhesus monkeys against all four serotypes of dengue virus.
- Author
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Raviprakash K, Wang D, Ewing D, Holman DH, Block K, Woraratanadharm J, Chen L, Hayes C, Dong JY, and Porter K
- Subjects
- Animals, Antibodies, Viral blood, Dengue immunology, Injections, Intramuscular, Macaca mulatta, Neutralization Tests, Viral Structural Proteins genetics, Viremia prevention & control, Adenoviridae genetics, Dengue prevention & control, Dengue Vaccines genetics, Dengue Vaccines immunology, Dengue Virus genetics, Dengue Virus immunology, Genetic Vectors
- Abstract
Nearly a third of the human population is at risk of infection with the four serotypes of dengue viruses, and it is estimated that more than 100 million infections occur each year. A licensed vaccine for dengue viruses has become a global health priority. A major challenge to developing a dengue vaccine is the necessity to produce fairly uniform protective immune responses to all four dengue virus serotypes. We have developed two bivalent dengue virus vaccines, using a complex adenovirus vector, by incorporating the genes expressing premembrane (prM) and envelope (E) proteins of dengue virus types 1 and 2 (dengue-1 and -2, respectively) (CAdVax-Den12) or dengue-3 and -4 (CAdVax-Den34). Rhesus macaques were vaccinated by intramuscular inoculation of a tetravalent dengue vaccine formulated by combining the two bivalent vaccine constructs. Vaccinated animals produced high-titer antibodies that neutralized all four serotypes of dengue viruses in vitro. The ability of the vaccine to induce rapid, as well as sustained, protective immune responses was examined with two separate live-virus challenges administered at 4 and 24 weeks after the final vaccination. For both of these virus challenge studies, significant protection from viremia was demonstrated for all four dengue virus serotypes in vaccinated animals. Viremia from dengue-1 and dengue-3 challenges was completely blocked, whereas viremia from dengue-2 and dengue-4 was significantly reduced, as well as delayed, compared to that of control-vaccinated animals. These results demonstrate that the tetravalent dengue vaccine formulation provides significant protection in rhesus macaques against challenge with all four dengue virus serotypes.
- Published
- 2008
- Full Text
- View/download PDF
46. A heterologous DNA prime-Venezuelan equine encephalitis virus replicon particle boost dengue vaccine regimen affords complete protection from virus challenge in cynomolgus macaques.
- Author
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Chen L, Ewing D, Subramanian H, Block K, Rayner J, Alterson KD, Sedegah M, Hayes C, Porter K, and Raviprakash K
- Subjects
- Animals, Encephalomyelitis, Venezuelan Equine immunology, Enzyme-Linked Immunosorbent Assay, Female, Immune System, Immunization, Immunoglobulin G chemistry, Interferon-gamma metabolism, Macaca, Male, Replicon, T-Lymphocytes virology, DNA Viruses chemistry, Encephalitis Virus, Venezuelan Equine genetics, Encephalomyelitis, Venezuelan Equine prevention & control, Viral Vaccines chemistry
- Abstract
A candidate vaccine (D1ME-VRP) expressing dengue virus type 1 premembrane and envelope proteins in a Venezuelan equine encephalitis (VEE) virus replicon particle (VRP) system was constructed and tested in conjunction with a plasmid DNA vaccine (D1ME-DNA) expressing identical dengue virus sequences. Cynomolgus macaques were vaccinated with three doses of DNA (DDD), three doses of VRP (VVV group), or a heterologous DNA prime-VRP boost regimen (DDV) using two doses of DNA vaccine and a third dose of VRP vaccine. Four weeks after the final immunization, the DDV group produced the highest dengue virus type 1-specific immunoglobulin G antibody responses and virus-neutralizing antibody titers. Moderate T-cell responses were demonstrated only in DDD- and DDV-vaccinated animals. When vaccinated animals were challenged with live virus, all vaccination regimens showed significant protection from viremia. DDV-immunized animals were completely protected from viremia (mean time of viremia = 0 days), whereas DDD- and VVV-vaccinated animals had mean times of viremia of 0.66 and 0.75 day, respectively, compared to 6.33 days for the control group of animals.
- Published
- 2007
- Full Text
- View/download PDF
47. Induction of bivalent immune responses by expression of dengue virus type 1 and type 2 antigens from a single complex adenoviral vector.
- Author
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Raja NU, Holman DH, Wang D, Raviprakash K, Juompan LY, Deitz SB, Luo M, Zhang J, Porter KR, and Dong JY
- Subjects
- Animals, Cell Line, Chlorocebus aethiops, Gene Expression, Humans, Mice, Vero Cells, Adenoviridae genetics, Antigens, Viral genetics, Antigens, Viral immunology, Dengue immunology, Dengue virology, Dengue Virus genetics, Dengue Virus immunology, Viral Vaccines genetics, Viral Vaccines immunology
- Abstract
There are approximately 100 million new cases of dengue (DEN) virus infection each year. Infection can result in illness ranging from a mild fever to hemorrhaging, shock, or even death. There are four serotypes of dengue virus (DEN1-4), and immunity to one serotype does not cross protect from infection with other serotypes. Currently there are no approved vaccines for dengue fever. In this report, we describe the construction of a bivalent dengue virus vaccine using a complex recombinant adenovirus approach to express multiple genes of DEN1 and DEN2 serotypes. In vaccinated mice, this vector induced humoral immune responses against all four dengue serotypes as measured by enzyme-linked immunosorbent assay. However, the neutralizing antibody responses were specific for DEN1 and DEN2 serotypes. Expansion of this vaccine development platform towards the DEN3 and DEN4 serotypes can lead towards the development of an adenovirus-based tetravalent dengue vaccine.
- Published
- 2007
48. Two complex, adenovirus-based vaccines that together induce immune responses to all four dengue virus serotypes.
- Author
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Holman DH, Wang D, Raviprakash K, Raja NU, Luo M, Zhang J, Porter KR, and Dong JY
- Subjects
- Animals, Cell Line, Chlorocebus aethiops, Dengue immunology, Dengue prevention & control, Dengue Virus classification, Humans, Mice, Mice, Inbred C57BL, Serotyping, Vero Cells, Adenoviridae, Dengue Vaccines immunology, Dengue Virus immunology, Genetic Vectors
- Abstract
Dengue virus infections can cause hemorrhagic fever, shock, encephalitis, and even death. Worldwide, approximately 2.5 billion people live in dengue-infested regions with about 100 million new cases each year, although many of these infections are believed to be silent. There are four antigenically distinct serotypes of dengue virus; thus, immunity from one serotype will not cross-protect from infection with the other three. The difficulties that hamper vaccine development include requirements of the natural conformation of the envelope glycoprotein to induce neutralizing immune responses and the necessity of presenting antigens of all four serotypes. Currently, the only way to meet these requirements is to use a mixture of four serotypes of live attenuated dengue viruses, but safety remains a major problem. In this study, we have developed the basis for a tetravalent dengue vaccine using a novel complex adenovirus platform that is capable of expressing multiple antigens de novo. This dengue vaccine is constructed as a pair of vectors that each expresses the premembrane and envelope genes of two different dengue virus serotypes. Upon vaccination, the vaccine expressed high levels of the dengue virus antigens in cells to mimic a natural infection and induced both humoral and cellular immune responses against multiple serotypes of dengue virus in an animal model. Further analyses show the humoral responses were indeed neutralizing against all four serotypes. Our studies demonstrate the concept of mimicking infections to induce immune responses by synthesizing dengue virus membrane antigens de novo and the feasibility of developing an effective tetravalent dengue vaccine by vector-mediated expression of glycoproteins of the four serotypes.
- Published
- 2007
- Full Text
- View/download PDF
49. A chimeric tetravalent dengue DNA vaccine elicits neutralizing antibody to all four virus serotypes in rhesus macaques.
- Author
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Raviprakash K, Apt D, Brinkman A, Skinner C, Yang S, Dawes G, Ewing D, Wu SJ, Bass S, Punnonen J, and Porter K
- Subjects
- Animals, Antibodies, Viral immunology, Antigens, Viral genetics, Antigens, Viral immunology, DNA Shuffling, Dengue immunology, Dengue virology, Dengue Virus classification, Dengue Virus drug effects, Dengue Virus genetics, Directed Molecular Evolution, Epitopes, Humans, Macaca mulatta, Male, Neutralization Tests, Recombinant Fusion Proteins immunology, Vaccines, DNA administration & dosage, Vaccines, DNA classification, Antibodies, Viral biosynthesis, Dengue prevention & control, Dengue Virus immunology, Vaccines, DNA immunology, Viral Vaccines immunology
- Abstract
DNA shuffling and screening technologies were used to produce chimeric DNA constructs expressing antigens that shared epitopes from all four dengue serotypes. Three shuffled constructs (sA, sB and sC) were evaluated in the rhesus macaque model. Constructs sA and sC expressed pre-membrane and envelope genes, whereas construct sB expressed only the ectodomain of envelope protein. Five of six, and four of six animals vaccinated with sA and sC, respectively, developed antibodies that neutralized all 4 dengue serotypes in vitro. Four of six animals vaccinated with construct sB developed neutralizing antibodies against 3 serotypes (den-1, -2 and -3). When challenged with live dengue-1 or dengue-2 virus, partial protection against dengue-1 was observed. These results demonstrate the utility of DNA shuffling as an attractive tool to create tetravalent chimeric dengue DNA vaccine constructs, as well as a need to find ways to improve the immune responses elicited by DNA vaccines in general.
- Published
- 2006
- Full Text
- View/download PDF
50. Evaluation of immunity and protective efficacy of a dengue-3 pre-membrane and envelope DNA vaccine in Aotus nancymae monkeys.
- Author
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Blair PJ, Kochel TJ, Raviprakash K, Guevara C, Salazar M, Wu SJ, Olson JG, and Porter KR
- Subjects
- Animals, Antibodies, Viral blood, Antigens, Viral genetics, Antigens, Viral immunology, Aotidae, Dengue Virus genetics, Dengue Virus immunology, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Humans, Neutralization Tests, RNA, Viral blood, Vaccines, DNA administration & dosage, Viral Envelope Proteins genetics, Viral Vaccines administration & dosage, Dengue immunology, Dengue prevention & control, Vaccines, DNA immunology, Viral Envelope Proteins immunology, Viral Vaccines immunology
- Abstract
A dengue (DEN) virus type 3 DNA vaccine expressing pre-membrane and envelope genes was tested for immunogenicity and protective efficacy in Aotus monkeys. Five of six vaccinated animals demonstrated moderate DEN-specific antibody responses as measured by ELISA and virus neutralization in vitro. By contrast, none of the six control animals developed detectable anti-DEN antibodies. When five vaccinated animals were challenged with live DEN-3 virus and viremia determined by PCR amplification of viral RNA in serum samples, one animal was completely protected and two were partially protected as indicated by a decrease in mean days of viremia. The results demonstrate the ability of the DEN-3 DNA vaccine to elicit a neutralizing antibody response and to partially protect against live virus challenge. These findings support the inclusion of this construct in a tetravalent DNA vaccine.
- Published
- 2006
- Full Text
- View/download PDF
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