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Neutralizing antibodies are associated with protection in animal models of coronavirus infection and vaccination.

dc.contributor.advisorFalzarano , Darryl
dc.contributor.committeeMemberJenkins , Emily
dc.contributor.committeeMemberMisra, Vikram
dc.contributor.committeeMemberHurk , Sylvia van den
dc.contributor.committeeMemberChelico, Linda
dc.creatorKulkarni, Swarali S
dc.creator.orcid0000-0002-2595-5968 2022
dc.description.abstractPrior to the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, human coronaviruses were primarily thought to cause relatively mild, respiratory disease. The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the introduction of a second highly pathogenic respiratory coronavirus, which continues to cause sporadic cases in Saudi Arabia. Dromedary camels are currently the only known animal reservoir for MERS-CoV and contact with camels is thought to be the source of over half of all primary human cases. Currently, several efforts are being made to develop a vaccine for camels as an intervention strategy to stop transmission from camels into humans. To date, there have been limited studies regarding the immune response from natural infection or vaccination in camels against MERS-CoV. Given the limitations in accessing and working with dromedary camels, an alpaca model which accurately recapitulates MERS-CoV infection in camels was established and subsequently, the neutralizing antibody response to infection and vaccination was characterized. The induction of neutralizing IgG1 and IgG3 isotypes following experimental MERS-CoV infection protected alpacas from subsequent re-infection. Similarly, a S1-based subunit vaccine delivered intramuscularly induced a similar IgG1 and IgG3 neutralizing antibody response, resulting in nearly complete protection following MERS-CoV challenge in alpacas. Moreover, the antibodies induced following infection as well vaccination were able to neutralize currently circulating MERS-CoV isolates from Saudi Arabian dromedary camels, despite of the presence of amino acid changes in the spike protein, the major target for neutralizing antibodies. This data suggests that the neutralizing antibody response may be useful for predicting protection following infection and vaccination. The recently emerged severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2), the causative agent of one of the worst pandemics, continues to circulate in humans. Since the isolation of the first strain of SARS-CoV-2, various variants of concern (VOC) have emerged with increased transmissibility and potential for immune escape. Using a hamster model, the neutralizing and cross-neutralizing activity for the B.1.1.7 and B.1.351 VOCs of SARS-CoV-2 were evaluated. The neutralizing activity varied depending on the VOC used for the challenge, with B.1.351 infection in hamsters inducing overall lower levels of neutralizing antibodies. These findings were consistent with differential neutralizing activity against VOCs induced by two different S1 based subunit vaccines. In the vaccine study, reduced neutralizing activity against B.1.351 resulted in reduced protection in hamsters. Finally, to demonstrate that neutralizing antibodies alone can provide protection from infection, two monoclonal antibodies; Ab1 and Ab8 targeting spike protein of SARS-CoV-2 were administered prophylactically and therapeutically in a hamster model of SARS-CoV-2 infection. Both monoclonal antibodies reduced SARS-CoV-2 viral titers as well as lung pathology in dose-dependent manner. Interestingly, higher concentrations of Ab8 were found in hamster lungs compared to Ab1 despite of being administered at comparable doses. The ability of monoclonal antibodies to reduce levels of virus and virus-induced pathology provides further supporting evidence that neutralizing antibodies likely play a critical role in protection from infection with respiratory CoV. These findings have major implications to design better vaccine and therapeutic strategies against the coronaviruses to provide a protection against severe disease.
dc.subjectNeutralizing antibodies
dc.subjectanimal models
dc.subjectCoronavirus vaccines
dc.titleNeutralizing antibodies are associated with protection in animal models of coronavirus infection and vaccination.
dc.type.materialtext Microbiology Microbiology of Saskatchewan of Philosophy (Ph.D.)


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