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- All Subjects: Vaccines
- Creators: Reyes del Valle, Jorge
Description
ABSTRACT In terms of prevalence, human suffering and costs dengue infections are the most important arthropod-borne viral disease worldwide. Dengue virus (DENV) is a mosquito-borne flavivirus and the etiological agent of dengue fever and dengue hemorrhagic fever. Thus, development of a safe and efficient vaccine constitutes an urgent necessity. Besides the traditional strategies aim at generating immunization options, the usage of viral vectors to deliver antigenic stimulus in order to elicit protection are particularly attractive for the endeavor of a dengue vaccine. The viral vector (MVvac2) is genetically equivalent to the currently used measles vaccine strain Moraten, which adds practicality to my approach. The goal of the present study was to generate a recombinant measles virus expressing structural antigens from two strains of DENV (DENV2 and DENV4) The recombinant vectors replication profile was comparable to that of the parental strain and expresses either membrane bound or soluble forms of DENV2 and DENV4 E glycoproteins. I discuss future experiments in order to demonstrate its immunogenicity in our measles-susceptible mouse model.
ContributorsAbdelgalel, Rowida (Author) / Reyes del Valle, Jorge (Thesis advisor) / Hogue, Brenda (Committee member) / Frasch, Wayne D (Committee member) / Arizona State University (Publisher)
Created2013
Description
Dengue virus infects millions of people every year. Yet there is still no vaccine available to prevent it. Here we use a neutralizing epitope determinant on the dengue envelope (E) protein as an immunogen to be vectored by a measles virus (MV) vaccine. However the domain III (DIII) of the dengue 2 E protein is too small to be immunogenic by itself. In order for it to be displayed on a larger particle, it was inserted into the amino terminus of small hepatitis B surface antigen (HBsAg, S) coding sequence. To generate the recombinant MV vector and verify the efficiency of this concept, a reverse genetics system was used where the MV vectors express one or two additional transcription units to direct the assembly of hybrid HBsAg particles. Two types of recombinant measles virus were produced: pB(+)MVvac2(DIII-S,S)P and pB(+)MVvac2(DIII-S)N. Virus recovered from pB(+)MVvac2(DIII-S,S)P was viable. An ELISA assay was performed to demonstrate the expression and secretion of HBsAg. Supernatant from MVvac2(DIII-S,S)P infected cells confirmed that hybrid HBsAg-domain III particles with a density similar to traditional HBsAg particles were released. Characteristics of the subviral particle have been analyzed for the successful incorporation of domain III. The replication fitness of the recombinant MV was evaluated using multi-step growth kinetics and showed reduced replication fitness when compared to the parental strain MVvac2. This demonstrates that viral replication is hindered by the addition of the two inserts into MV genome. Further analysis of MVvac2(DIII-S)N is needed to justify immune response studies in a small animal model using both of the generated recombinant vectors.
ContributorsHarahap, Indira Saridewi (Author) / Reyes del Valle, Jorge (Thesis director) / Hogue, Brenda (Committee member) / Misra, Rajeev (Committee member) / Barrett, The Honors College (Contributor) / T. Denny Sanford School of Social and Family Dynamics (Contributor) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor)
Created2014-05
Description
The development of safe and effective vaccines has been one of the greatest public achievements of the 20th century. However, there is still considerable public debate about the relative health costs and benefits of vaccines, and the information and misinformation spread through these debates can have a direct impact on vaccination and whether or not herd immunity will continue in the United States for different diseases. To understand perceptions of vaccine risks and effectiveness among young adults in the U.S., this study describes Arizona State University students' perceptions of the harms and benefits of vaccines. A preliminary free list (n=30) identified what vaccines ASU college students were most likely to recall spontaneously. The six vaccines most commonly mentioned by ASU students were: influenza (flu), chickenpox, HPV, polio, MMR, and smallpox. Using these top six vaccines, we then developed a second survey about the knowledge and perceptions of each of these vaccines and vaccines as a whole. We found that students generally perceived vaccines as safe and important to their health, but they maintained an overall lack of understanding of how vaccines work and what they protect against. While this study is only a preliminary investigation into the perceptions of ASU college students on six commonly mentioned vaccines, this could lead to investigations on how to educate and promote the usage of vaccines to college students.
ContributorsGilson, Jacob (Co-author) / Sutton, Carly (Co-author) / Hruschka, Daniel (Thesis director) / Ruth, Alissa (Committee member) / W. P. Carey School of Business (Contributor) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Vaccines against the arthropod-borne dengue virus (DENV) are still commercially nonexistent. A subunit immunization strategy may be of value, especially if a safe viral vector acts as a biologically active adjuvant. The DENV envelope protein (E), the main target for neutralizing immune responses, has three conformational domains. The immunoglobulin-like and independently folding domain III (DIII) contains epitopes that elicit highly specific neutralizing antibodies. The hepatitis B small surface antigen (HBsAg, S) was used as a scaffold to display DENV 2 DIII on a virus-like particle (VLP). A measles virus (MV) was engineered to vector HBsAg and the hybrid glycoprotein DIII-HBsAg in two different loci (DIII-S). Despite the relatively deleterious effect on replication caused by the insertion of two transcription cassettes, the recombinant virus MVvac2(DIII-S,S)P induced the secretion of DIII-S hybrid VLP with a similar sucrose density as HBsAg particles (1.10-1.12g/ml) and peaked at 48 h post-infection producing 1.3x106 TCID50/ml infectious MV units in vitro. A second recombinant virus, MVvac2(DIII-S)N, was engineered to vector only the hybrid DIII-S. However, it did not induce the secretion of hybrid HBsAg particles in the supernatant of infected cells. The immunogenicity of the recombinant viruses was tested in a MV-susceptible small animal model, the experimental group which received two 105 TCID50 I.P. doses of MVvac2(DIII-S,S)P in a 28 day interval developed a robust immune response against MV (1:1280), HBsAg (787 mIU/ml) and DENV2 (Log10 neutralization index of 1.2) on average. In summary, it is possible to display DENV E DIII on hybrid HBsAg particles vectored by MV that elicit an immune response. This forms the basis for a potential vaccine platform against DENV.
ContributorsHarahap, Indira (Author) / Reyes del Valle, Jorge (Thesis advisor) / Hogue, Brenda G (Thesis advisor) / Lake, Douglas (Committee member) / Mason, Hugh (Committee member) / Arizona State University (Publisher)
Created2015
Description
Background: This study examines how pro-vaccine flu messages, guided by the Extended Parallel Process Model (EPPM), affect parents’ intentions to vaccinate their children.
Methods: Parents of children six months to five years old (N = 975) were randomly exposed to one of four high-threat/high-efficacy messages (narrative, statistical, combined, control) and completed a follow-up survey. Differences between message conditions were assessed with one-way ANOVAs, and binary logistic regressions were used to show how constructs predicted intentions.
Results: There were no significant differences in the ANOVA results at p = .05 for EPPM variables or risk EPPM variables. There was a significant difference between message conditions for perceived manipulation (p = 0.026), authority, (p = 0.024), character (p = 0.037), attention (p < .000), and emotion (p < .000). The EPPM model and perceptions of message model (positively), and the risk EPPM model and fear control model (negatively), predicted intentions to vaccinate. Significant predictor variables in each model at p < .05 were severity (aOR = 1.83), response efficacy (aOR = 4.33), risk susceptibility (aOR = 0.53), risk fear (aOR = 0.74), issue derogation (aOR = 0.63), perceived manipulation (aOR = 0.64), character (aOR = 2.00), and personal relevance (aOR = 1.88). In a multivariate model of the significant predictors, only response efficacy significantly predicted intentions to vaccinate (aOR = 3.43). Compared to the control, none of the experimental messages significantly predicted intentions to vaccinate. The narrative and combined conditions significantly predicted intentions to search online (aOR = 2.37), and the combined condition significantly predicted intentions to talk to family/friends (aOR = 2.66).
Conclusions: The EPPM may not be effective in context of a two-way threat. Additional constructs that may be useful in the EPPM model are perceptions of the message and fear control variables. One-shot flu vaccine messages will be unlikely to directly influence vaccination rates; however they may increase information-seeking behavior. The impact of seeking more information on vaccination uptake requires further research. Flu vaccine messages should be presented in combined form. Future studies should focus on strategies to increase perceptions of the effectiveness of the flu vaccine.
Methods: Parents of children six months to five years old (N = 975) were randomly exposed to one of four high-threat/high-efficacy messages (narrative, statistical, combined, control) and completed a follow-up survey. Differences between message conditions were assessed with one-way ANOVAs, and binary logistic regressions were used to show how constructs predicted intentions.
Results: There were no significant differences in the ANOVA results at p = .05 for EPPM variables or risk EPPM variables. There was a significant difference between message conditions for perceived manipulation (p = 0.026), authority, (p = 0.024), character (p = 0.037), attention (p < .000), and emotion (p < .000). The EPPM model and perceptions of message model (positively), and the risk EPPM model and fear control model (negatively), predicted intentions to vaccinate. Significant predictor variables in each model at p < .05 were severity (aOR = 1.83), response efficacy (aOR = 4.33), risk susceptibility (aOR = 0.53), risk fear (aOR = 0.74), issue derogation (aOR = 0.63), perceived manipulation (aOR = 0.64), character (aOR = 2.00), and personal relevance (aOR = 1.88). In a multivariate model of the significant predictors, only response efficacy significantly predicted intentions to vaccinate (aOR = 3.43). Compared to the control, none of the experimental messages significantly predicted intentions to vaccinate. The narrative and combined conditions significantly predicted intentions to search online (aOR = 2.37), and the combined condition significantly predicted intentions to talk to family/friends (aOR = 2.66).
Conclusions: The EPPM may not be effective in context of a two-way threat. Additional constructs that may be useful in the EPPM model are perceptions of the message and fear control variables. One-shot flu vaccine messages will be unlikely to directly influence vaccination rates; however they may increase information-seeking behavior. The impact of seeking more information on vaccination uptake requires further research. Flu vaccine messages should be presented in combined form. Future studies should focus on strategies to increase perceptions of the effectiveness of the flu vaccine.
ContributorsHall, Sarah (Author) / Jehn, Megan (Thesis advisor) / Mongeau, Paul (Committee member) / Hruschka, Daniel (Committee member) / Margolis, Eric (Committee member) / Arizona State University (Publisher)
Created2015
Description
Despite the approval of a Dengue virus (DV) vaccine in five endemic countries, dengue prevention would benefit from an immunization strategy highly immunogenic in young infants and not curtailed by viral interference. Problematically, infants younger than 9 year of age, whom are particularly prone to Dengue severe infection and death, cannot be immunized using current approved DV vaccine. The most important issues documented so far are the lack of efficiency and enhancement of the disease in young seronegative recipients, as well as uneven protection against the four DV serotypes. Based on data from clinical trials that showed enhanced performance of dengue vaccines when the host has previous anti-flaviviral immunity, I proposed here an attractive solution to complement the current vaccine: a recombinant measles vaccine vectoring dengue protective antigens to be administered to young infants. I hypothesized that recombinant measles virus expressing Dengue 2 and 4 antigens would successfully induce neutralizing responses against DV2 and 4 and the vaccine cocktail of this recombinant measles can prime anti-flaviviral neutralizing immunity. For this dissertation, I generated and performed preclinical immune assessment for four novel Measles-Dengue (MV-DV) vaccine candidates. I generated four MVs expressing the pre membrane (prM) and full length or truncated (90%) forms of the major envelope (E) from DV2 and DV4. Two virus, MVvac2-DV2(prME)N and MVvac2-DV4(prME), expressed high levels of membrane associated full-length E, while the other two viruses, MVvac2-DV2(prMEsol)N and MVvac2-DV4(prMEsol)N, expressed and secreted truncated, soluble E protein to its extracellular environment. The last two vectored vaccines proved superior anti-dengue neutralizing responses comparing to its corresponding full length vectors. Remarkably, when MVvac2-DV2/4(prMEsol)N recombinant vaccines were combined, the vaccine cocktail was able to prime cross-neutralizing responses against DV 1 and the relatively distant 17D yellow fever virus attenuated strain. Thus, I identify a promising DV vaccination strategy, MVvac2-DV2/4(prMEsol)N, which can prime broad neutralizing immune responses by using only two of the four available DV serotypes. The current MV immunization scheme can be advantageus to prime broad anti-flaviviral neutralizing immunity status, which will be majorly boosted by subsequent chimeric Dengue vaccine approaches.
ContributorsAbdelgalel, Rowida (Author) / Reyes del Valle, Jorge (Thesis advisor) / Mason, Hugh (Thesis advisor) / Lake, Douglas (Committee member) / Stout, Valerie (Committee member) / Frasch, Wayne (Committee member) / Arizona State University (Publisher)
Created2016