Project Details
Description
Abstract
The COVID-19 pandemic has had a profound, global impact on public health. Of the 120,000,000 cases
documented world-wide, over 30 million cases have occurred in the Unites States, with >530,000 COVID
deaths to date. Considerable progress in control of the pandemic has been realized in the USA by licensure of
three effective vaccines, and many additional immunization strategies are now in preclinical study and clinical
trials. An emerging consensus is that an effective vaccine will require responses to the viral-encoded spike (S)
protein, in particular, its receptor-binding domain (RBD). However, uncertainties remain about the optimal
expression platform(s), as well as concerns for untoward effects conferred by vaccination, including the
concern of potential antibody-dependent enhancement of infection. Another major issue is the need for
vaccine-mediated protection of the pregnant patient and the fetus/neonate. Although congenital and
perinatal transmission of SARS-CoV-2 infection has been documented, and serious COVID-19 disease in
children is increasingly described, no strategy for immunization during pregnancy has been forthcoming.
To help inform and direct future vaccine strategies for COVID-19 disease, we will address these areas of
knowledge deficiency using a guinea pig model of SARS-CoV-2 vaccination. Our plan is to test hypotheses
about optimized COVID-19 vaccine strategies using a Pichinde virus (PICV) vector. PICV is an enveloped RNA
virus within the Arenavirus family and is not known to cause disease in humans or most animals. We have
developed a PICV-based viral vector rP18tri and demonstrated it as a safe, effective, and versatile vaccine
vector that elicits a balanced antibody and T cell response. We have preliminary data showing that a novel
rP18tri-based SARS-CoV-2 S RBD domain vaccine can induce specific antibodies, including neutralizing
antibodies, in mice. In Aim 1, we will test the hypothesis that this PICV-vectored vaccine (and other vaccines
with improved antigen design) will demonstrate immunogenicity in guinea pigs, with enhanced immune
responses compared to an MPL-adjuvanted RBD protein vaccine. We will compare mucosal, subcutaneous
and intramuscular routes of immunization, comparing ELISA and neutralization titers. We will also include
mucosal read-outs, including IgA responses, and will test the hypothesis that the PICV vector is associated
with enhanced IFN-γ ELISPOT responses (compared to adjuvanted RBD vaccine). In Aim 2, we will examine
vaccine safety and transplacental antibody transfer in neonatal guinea pigs following immunization in early
pregnancy, comparing PICV vectored and subunit RBD vaccines in a dam-to-newborn antibody transfer model.
We will examine serum from newborn pups to test the hypothesis that virus-neutralizing antibodies cross the
placenta. These experiments have high relevance to human health, and will lay the groundwork for future
SARS-CoV-2 challenge studies in the guinea pig pregnancy model that, in turn, can help clarify the optimal
vaccine strategies to control congenital and perinatally-acquired COVID-19 disease in women and infants.
Status | Finished |
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Effective start/end date | 11/1/21 → 10/31/23 |
Funding
- National Institute of Allergy and Infectious Diseases: $232,500.00
- National Institute of Allergy and Infectious Diseases: $193,750.00
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