Thesis (Ph. D.)--University of Queensland, 2003. / Includes bibliographical references.

Objectives This study focuses on the evaluation of the use of vaccine in the prevention of severe acute gastroenteritis in the community in the literature. The objectives of this project report include an in depth review of the effectiveness and cost effectiveness of rotavirus vaccination for severe acute gastroenteritis in low and middle income countries (developing countries). Methods Publications were identified using computerized bibliographic searches in PubMed (for the period from October 1994 to July 2012). The keywords “effective*”, “vaccin*”, “rotavirus” , “Randomized controlled trial” were used to search for relevant information. Also the keywords “轮状病毒”, “疫苗” , “随机对照试验” were used to search for relevant information in China Journals Full-text Database(中国期刊全文数据库). Selection criteria: SSRandomized controlled trials (RCT) in children (<5 years old) comparing rotavirus RV1/RV5/LLR vaccines for use with (1) placebo, (2) no intervention, or (3) another RV1/RV5/LLR vaccine. Once the identified articles had been screened by the inclusion and exclusion criteria, the content of each was evaluated in relation to the two research questions. International guidelines: CONSORT (for RCT) was also followed in the quality assessment process. Results In our review, there were 9 studies included and 2 of them were graded A(i.e. good quality), 5 graded B(i.e. medium quality) and 2 graded C(i.e. poor quality). For the two Grade A studies, vaccine effectiveness was estimated to be 39.3% and 48.3%. For 5 Grade B studies, vaccine effectiveness was estimated to be 19.2% to 63.9%. For 2 Grade C studies, vaccine effectiveness was estimated to be 10.6% and 74.3%. There is a smaller range in vaccine effectiveness in grade A studies. In contrast, there is a greater range in vaccine effectiveness in grade B and C studies. Many low and middle income countries may not have enough training in conducting RCT. However, the Grade A studies showed that rotavirus vaccine is effective. Our review also showed that authors from most of the low income countries suggested that rotavirus vaccine is cost effective to very cost effective, while those from middle income countries suggested that the cost of the vaccine is the key factor. Conclusion This review showed evidence of effectiveness of rotavirus vaccine and cost-effectiveness in low and middle income countries (developing countries). China has a huge population and similar situation with other developing countries, hence it is useful to conduct a study on cost-effectiveness on universal vaccination in the near future. / published_or_final_version / Public Health / Master / Master of Public Health

Objective Data on immunogenicity of hepatitis A vaccines (including inactivated and live attenuated vaccine) have been reviewed using a systematic approach in Chinese children. Our mission is to provide a comprehensive review of evidence that whether vaccine types, booster, dosage and age could affect immunogenicity. Methodology A systematic literature review was conducted including all studies reporting on immunogenicity of hepatitis A vaccine. The outcomes considered were hepatitis A Geometric Mean Concentration (GMC) and sero-conversion proportions measured by anti-HAV antibodies after immunization. Results 20 studies were identified from PubMed and Google Scholar according to searching concept. 7 manuscripts met our inclusion criteria. The Sero-conversion proportions of inactivated vaccine (Havrix and Healive)and live attenuated vaccine(H2) were close to 100% after 4-week injection, and GMC of them were 67.2mIU/ml, 71.3mIU/ml and 46.8mIU/ml respectively. Another live attenuated vaccine (LA-1) has been reported no significant differences fromH2 in terms of the Sero-conversion proportions and GMC. Booster demonstrated a stronger response both in inactivated and live attenuated vaccines. In terms of dosage, although more dosage could offer higher GMC, adequate dosage was recommended. In addition, the GMC of less dosage one was significantly lower than that of more dosage after 24 months of first injection. Conclusion Available data indicate that immunogenicity of inactivated and live attenuated Hepatitis A is extremely similar, and both could provide protection for Chinese children. Using booster of inactivated and live attenuated hepatitis A vaccine can increase the immunogenicity. / published_or_final_version / Public Health / Master / Master of Public Health

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 281-328).

Thesis (Ph.D.) - University of St Andrews, December 2007.

Orf virus (ORFV) has the potential to be developed as a vaccine vector. Its ability to stimulate non-specific as well as specific immune responses in permissive and non-permissive hosts stands it in good stead to be utilised as such a tool. The fusion of immunogenic peptides to vaccinia virus (VACV) structural proteins have been shown to improve their immunogenicity due to presentation of the foreign antigens in a particulate form that can stimulate both B and T cells. The aims of this study were to fuse foreign antigens to ORFV structural proteins to demonstrate proof-of-concept that such surface display could also render the foreign antigens more immunogenic. Little is known about ORFV structure and morphogenesis. When this study commenced, the ORFV genome had recently been sequenced and this revealed a large number of homologues in common with VACV. It was thus assumed that both viruses may share structural similarities and that ORFV also assumes the different morphological forms such as the mature virion (MV) and extracellular virion (EV) that are present in VACV. The MV and EV forms are both infectious, with the EV containing an additional membrane acquired from the trans-Golgi network during viral morphogenesis. Furthermore, specific viral proteins are associated with both the MV and EV membranes. Six ORFV structural proteins ORFV 089, 10 kDa, F1, that are homologues of structural membrane proteins A13, A27 and H3 of VACV MVs, together with ORFV 109, ORFV 110 and B2, that are homologues of structural membrane proteins A33, A34 and F13 of VACV EVs were selected as possible candidates for manipulation. At present, there is some information available only for 10 kDa, F1 and B2. The 10 kDa is required for virus assembly, F1 for mediating cell attachment while B2 has been shown to induce significant antibody responses in sheep. Indeed proteomic analyses predicted similarities in the topologies of all of these proteins with their VACV counterparts. Using this information, preliminary studies were conducted to generate recombinant ORFVs (rORFVs) which had FLAG fused to the terminus of the protein that was exposed on the surface of the virus particle. Three rORFVs 10 kDa, F1L and 110 were successfully generated. Immunogold labelling of FLAG proteins on virus particles isolated from lysed cells showed that FLAG-10 kDa and FLAG-F1 were displayed on the surface of MV particles whereas FLAG-ORFV 110 could not be detected. Western blot analyses of solubilised recombinant ORFV 110-FLAG particles revealed that FLAG-ORFV 110 was abundant and undergoes post-translational modification indicative of endoplasmic reticulum trafficking whereas FLAG-10 kDa and FLAG-F1 did not appear to be subjected to post-translational modifications. Fluorescent microscopy confirmed the prediction that ORFV 110-FLAG localised to the Golgi in virus-infected cells and immunogold labelling of EVs showed that ORFV110-FLAG became exposed on the surface of EV-like particles as a result of egress from the cell, suggesting that the membranes had been acquired from the Golgi. These modifications also appeared to have minimal effect on the infectivity of these rORFVs. The study was extended by replacing the small FLAG peptide with an immunogenic protein (EG95), derived from the oncosphere of the zoonotic parasite Echinococcus granulosus. This protein is known to confer protection in immunised animals. Three rORFVs were generated in which a truncated version of the protein, EG95[Delta]TM, was fused to 10 kDa in the absence (rORFV 699) or presence (rORFV 700) of a linker, and also to F1 (rORFV 701). Western blot analyses of these solubilised particles demonstrated that the fusion proteins appeared to be post-translationally modified while immunogold labelling using anti-EG95 monoclonal antibodies successfully demonstrated the surface labelling on these rORFVs. In order to test the immunogenicity of these rORFVs, prime-boost experiments in sheep were conducted using rORFVs 699, 700 and 701 and a glutathione-S-transferase (GST-EG95) based vaccine. The results showed the production of EG95-specific antibodies. In particular, antibody production by group rORFV 701 compared favourably with a control group that was primed and boosted by GST-EG95 vaccine. This was despite the slightly slower growth rates of rORFVs 700 and 701 and the decreased infectivity of all three rORFVs discovered in in vitro experiments. In conclusion, these studies indicated the feasibility of this strategy to manipulate ORFV structural proteins for use as an agent for vaccine delivery.

The lack of an effective HIV vaccine calls for efforts to investigate the mechanism of protective immunity against AIDS viruses. It has been previously demonstrated that the live replication-competent modified vaccinia virus Tiantan (MVTT) is superior to non-replication vaccinia MVA in inducing high levels of neutralizing antibodies against SARS-CoV infection via mucosal vaccination. Therefore, the hypothesis was that MVTT could be a better HIV vaccine vector given its highly attenuated phenotypes such as no neurovirulence and safe in severe combined immunodeficiency disease (SCID) mice. Here, a recombinant MVTT expressing SIVmac239 Gag-Pol and Env (rMVTTSIVgpe) was constructed and its immunogenicity was assesed when administered via different routes using homologous prime-boost strategies or in heterologous regimens boosted with a recombinant adenovirus-based vaccine inserted matched SIVmac239 genes (rAd5SIVgpe). Results show that the heterologous prime-boost immunization with rMVTTSIVgpe and rAd5SIVgpe induces significantly greater humoral and T cell responses specific to SIV Gag, Pol and Env than homologous inoculations in mice with remarkable improvements in quality and quantity. The further study comparing different combinations of rMVTTSIVgpe and rAd5SIVgpe demonstrates that the rMVTTSIVgpe prime-rAd5SIVgpe boost regimens elicit systemic CD8+ T cell responses with augmented magnitude and polyfunctionality, as compared with rAd5SIVgpe-rMVTTSIVgpe and rAd5SIVgpe-rAd5SIVgpe regimens. Priming with rMVTTSIVgpe also increases frequencies of gut-homing Gag-specific CD8+ T cells (CCR9+47+ and CCR6+47+) and levels of CD8+ T cell ELISPOT responses against Gag, Pol and Env in mesenteric lymph nodes (MLNs) post-boost. The mucosal route of immunization is essential for rMVTTSIVgpe to induce rectal IgG with detectable neutralizing activity against SIVmac1A11. Furthermore, the regimen involving mucosal prime with rMVTTSIVgpe followed by systemic boost with rAd5SIVgpe proves to be efficient in protecting monkeys from mucosal challenge of a high dose of SIVmac239, a CCR5-tropic strain with high pathogenicity and neutralization-resistance. SIV-specific T cell ELISPOT responses specific to Gag and Pol but not Env and the frequency of Gag-specific IFN-+TNF-+CD8+ effector memory T cells (TEM) are likely associated with virological control after challenge. Mucosal immunity induced by this vaccination strategy also has important implications to the effectiveness of protection against disease progression. A hypothesis was generated that removal of non-protective but immune dominant determinant of SIVmac239 Env may drive antibody responses to protective domains. It was found that the neutralization-resistance of SIVmac239 could be partially explained by its high immunogenicity in eliciting CD4-induced neutralizing antibodies, which are unable to protect the CCR5-binding site due to the conformational masking and steric restriction. It was discovered that the immunodominance of CD4-induced neutralizing antibodies on SIV envelope is determined by a single highly conserved N-linked glycosylation site (N277) in the C2 domain. Substitution of this N-linked site abolishes viral entry and the immunogenicity of the CD4i domain while promotes V2-specific antibody responses, which have recently been identified as an important immunological correlate to HIV-1/SIV protection. Our findings demonstrate the concept that B cell immunodominance is relative and eliminating the dominant antigenic region can result in redirection of B cell recognition, which have critical implications for immunogen design and the development of protective antibody-based HIV vaccine. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

published_or_final_version / Zoology / Master / Master of Philosophy

Thesis (Ph. D.)--Rutgers University, 2007. / "Graduate Program in Pharmaceutical Science." Includes bibliographical references (p. 167-189).

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.