Date of Award

5-31-2022

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Yang Wang

Second Advisor

Lisa Cavacini

Third Advisor

Rick Kesseli

Abstract

Antibodies are thought to be one of the most important immune components of the body’s defense against infectious agents, including bacteria and viruses. They are highly specific with the potential to be used for both prevention and treatment of infectious diseases. Protection from infectious disease through vaccination is often time consuming that requires several boosters to elicit a protective immune response. Passive immunization with antibody infusion however provides immediate protection with much less variability among the patients. Serum therapy was used in the early 19th century as a cost effective and efficient anti-microbial therapy to a wide range of infectious diseases. Advancement of technology today has led to many monoclonal antibody discovery platforms. To date there have been more than 100 approved monoclonal antibodies for human use. Monoclonal antibodies are now considered a feasible therapeutic modality for various infectious disease targets, including newly emerging viral pathogens such as SARS-CoV-2 which is an ongoing and significant public health concern, as well as pathogens that have long been known, such as Rabies and Lyme disease. In this dissertation, I explored antibody prevention of different emerging infectious diseases including SARS-CoV-2, Rabies and Lyme diseases. As an ongoing effort to help eradicate the spread of SARS-CoV-2, I discovered and characterized a cross-reactive human IgA monoclonal antibody, MAb362. This antibody cross neutralizes both SARS-CoV and SARS-CoV-2 spike proteins and competitively blocks ACE2 receptor binding, by overlapping the ACE2 structural binding epitope. When converted to secretory IgA, MAb326 also neutralizes authentic SARS-CoV-2 virus while the IgG isotype shows no neutralization. Our results suggest that SARS-CoV-2 specific IgA antibodies, such as MAb362, may provide effective immunity against SARS-CoV-2 by inducing mucosal immunity within the respiratory system, a potentially critical feature of an effective vaccine. A second pathogen studied in this dissertation is Rabies virus which is a zoonotic pathogen with both wildlife and domesticated animal reservoirs. Human infection with rabies virus produces an acute illness with rapidly progressive central nervous system manifestations that almost invariably progress to death if not treated properly. Here I explored the potential uses of a fully human anti-Rabies monoclonal antibody (HuMabs) against North American isolates. Two HuMab cocktails are proposed (R172 [Rab1+Rab2] and R173 [Rab1+Rab3]) as an alternative PEP for the existing human rabies immunoglobulin hRIG. These HuMabs fully neutralize North American isolates both in in vitro and in vivo neutralization assays. The last pathogen I studied is Borrelia spirochete that related to the cause of human Lyme disease. I explored the potential of using HuMabs as pre-exposure prophylaxis against tick transmission of Borrelia spirochetes to humans. There is significant morbidity from Lyme disease worldwide, specifically in the USA. A panel of HuMabs developed against the outer surface protein A (OspA) were shown to correlate with protection from infection with Borrelia burgdorferi, the primary cause of Lyme disease in the United States. In this dissertation, I described and characterized a panel of OspA- specific HuMabs that are borreliacidal against a broad range of Borrelia genospecies. These lead HuMabs can prevent the transmission of Borrelia from ticks to mice and support exploring administration of anti-OspA antibodies as pre-exposure prophylaxis to prevent Lyme disease.

Comments

Free and open access to this Campus Access Dissertation is made available to the UMass Boston community by ScholarWorks at UMass Boston. Those not on campus and those without a UMass Boston campus username and password may gain access to this dissertation through resources like Proquest Dissertations & Theses Global or through Interlibrary Loan. If you have a UMass Boston campus username and password and would like to download this work from off-campus, click on the "Off-Campus UMass Boston Users" link above.

Download
Off-Campus UMass Boston Users

Share

COinS