Immunogenicity and protection efficacy of subunit-based smallpox vaccines using variola major antigens
Student AuthorsMichael G. Kishko
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
KeywordsAmino Acid Sequence; Animals; Antigens, Viral; Body Weight; Cell Line; Chemoprevention; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Feasibility Studies; Female; Humans; Immunization Schedule; Immunoglobulin G; Kidney; Mice; Mice, Inbred BALB C; Models, Animal; Molecular Sequence Data; Neutralization Tests; Sequence Homology, Amino Acid; Smallpox; Smallpox Vaccine; Vaccines, Attenuated; Vaccines, DNA; Vaccines, Subunit; Vaccinia virus; Variola virus; *Viral Vaccines
Immunology and Infectious Disease
Medicine and Health Sciences
MetadataShow full item record
AbstractThe viral strain responsible for smallpox infection is variola major (VARV). As a result of the successful eradication of smallpox with the vaccinia virus (VACV), the general population is no longer required to receive a smallpox vaccine, and will have no protection against smallpox. This lack of immunity is a concern due to the potential for use of smallpox as a biological weapon. Considerable progress has been made in the development of subunit-based smallpox vaccines resulting from the identification of VACV protective antigens. It also offers the possibility of using antigens from VARV to formulate the next generation subunit-based smallpox vaccines. Here, we show that codon-optimized DNA vaccines expressing three VARV antigens (A30, B7 and F8) and their recombinant protein counterparts elicited high-titer, cross-reactive, VACV neutralizing antibody responses in mice. Vaccinated mice were protected from intraperitoneal and intranasal challenges with VACV. These results suggest the feasibility of a subunit smallpox vaccine based on VARV antigen sequences to induce immunity against poxvirus infection.
SourceVirology. 2008 Feb 5;371(1):98-107. Epub 2007 Oct 24. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32804
Related ResourcesLink to Article in PubMed
Showing items related by title, author, creator and subject.
No, vaccine side effects don’t tell you how well your immune system will protect you from COVID-19Finberg, Robert W. (2021-04-19)It's normal for different people to mount stronger or weaker immune responses to a vaccine, but post-shot side effects won't tell you which you are. Robert Finberg is a physician who specializes in infectious diseases and immunology at the Medical School at the University of Massachusetts. He explains how this perception doesn’t match the reality of how vaccines work.
FC Receptor-Mediated Activities of Env-Specific Monoclonal Antibodies Generated from Human Volunteers Receiving a DNA Prime-Protein Boost HIV Vaccine: A DissertationCosta, Matthew R. (2016-10-12)Human immunodeficiency type 1 (HIV-1) is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years’ infection and as a result, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that a moderate protection is possible, which may correlate with antibody dependent cellular cytotoxicity (ADCC) activity. Previous studies in the Lu lab demonstrated that in an HIV-1 vaccine phase I trial, DP6-001, a polyvalent Env DNA prime-protein boost formulation, could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities along with multiple Fc mediated effector functions. I developed a protocol for the production and analysis of HIV-1 Env-specific human monoclonal antibodies (mAbs) isolated from these DP6-001 vaccinees. By utilizing a labeled gp120 bait to isolate Env specific B cells, paired heavy and light chain immunoglobulin (Ig) genes were cloned and allowed for the production of monoclonal antibodies with specificity for gp120. By using this protocol, 13 isolated mAbs from four DP6-001 vaccinees showed broad binding activities to gp120 proteins of diverse subtypes, both autologous and heterologous to vaccine immunogens, with mostly conformational epitopes and a few V3 and C5 specific mAbs. Equally cross-reactive Fc-mediated functional activities, including ADCC and antibody dependent cellular phagocytosis (ADCP), were present with both immune sera and isolated mAbs, confirming the induction of non-neutralizing functional antibodies by the DNA prime- protein boost vaccination. Elicitation of broadly reactive mAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV-1 vaccine design.
Adjuvant-Specific Serum Cytokine Profiles in the Context of a DNA Prime-Protein Boost HIV-1 Vaccine: A DissertationBuglione-Corbett, Rachel (2013-04-29)In recent years, heterologous prime-boost vaccination constructs have emerged as a promising strategy to generate broad and protective immunity against a variety of pathogens. The utility of DNA vaccination in priming the immune system, in particular, has improved the immunogenicity of vaccines against difficult pathogens such as HIV-1. In addition, many vaccine formulations include an adjuvant to augment immune responses. However, the mechanisms and profiles of many adjuvants remain largely unknown, particularly in the context of such combination immunization approaches. My thesis research studied the effects of several adjuvants, QS-21, aluminum hydroxide, MPL, and ISCOMATRIX™ adjuvant in the context of a previously described pentavalent HIV-1 Env DNA prime-protein boost vaccine, DP6-001. In a murine model, we quantified HIV antigen-specific humoral and T cell responses, as well as pro-inflammatory serum cytokine and chemokines, both shortly after immunization and at the termination of studies. Our data indicates that each candidate adjuvant generates a unique pattern of biomarkers as well as improved immunogenicity in the context of the DP6-001 DNA prime-protein boost vaccine. Additionally, we examined the impact of several innate signaling pathways on the adaptive immunity raised by DP6-001 and adjuvants, as well as on the unique serum cytokine profiles. These studies provide valuable information in selection of an adjuvant for inclusion in future prime-boost strategies, with the goal of enhancing immunogenicity while minimizing reactogenicity. Furthermore, these studies provided insight about the utility of different current adjuvants in a prime-boost formulation, and the unique immune environment induced by DNA priming.