Viral Vectored COVID-19 Vaccines in a Guinea Pig Perinatal Infection Model

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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.