#56 Does Cytomegalovirus (CMV) Status Impact the Host Response to SARS-CoV-2?
Authors: Isabell Stephen 
Published: June 2022

Abstract

Background
Cytomegalovirus (CMV) seropositivity has a significant immunomodulating over the life course, both with respect to responses to infections and responses to vaccines. For example, influenza vaccine response is known from multivariate analyses to be reduced by CMV seropositivity in elderly individuals. In patients with COVID-19, evidence suggests there are interactions between SARS-CoV-2 and CMV. CMV seropositives may have more severe COVID disease, and patients recovering from COVID often reactivate latent CMV, leading to end-organ CMV disease. This study aimed to test two hypotheses: 1) that vectored vaccines based on attenuated arenaviruses demonstrate equivalent immunogenicity to adjuvanted protein subunit spike (S) vaccines in a guinea pig vaccine model; 2) that CMV seropositivity impacts the immune response to S protein-based vaccines.

Method
Guinea pigs (n=3 per group) were vaccinated with a 2-dose series of an attenuated arenavirus (Pichinde virus) S protein-vectored vaccine by intranasal (IN; n=4) or intramuscular (IM) route at a dose of 1x10^5 PFU. A 2-dose series of Addavax-adjuvanted S protein (RBD) vaccine (20 μg) was administered in parallel by IM or subcutaneous (SC) route. Matched control animals (Pichinde vector-only, or adjuvant only) were sham-vaccinated. The Pichinde-vector virus can be engineered with certain points of interest. It then can be transfected into other cells in the body. Blood was collected pre-vaccination and post-vaccination for CMV serology, and for SARS-CoV-2 S protein-specific ELISA, and for western blot analyses. Vaccine comparisons were conducted in CMV seronegative and CMV seropositive animals, to assess for an impact of CMV seropositivity on COVID vaccine response.

Results
Nine of 25 animals tested positive for CMV antibodies prior to vaccination; 6 were in the S protein vaccine group, allowing comparison of the impact of CMV seropositivity to immune response compared to CMV negatives. COVID S ELISA antibodies were comparably induced by both vaccination routes. The magnitude of the Pichinde vectored vaccine response was similar to adjuvanted recombinant protein vaccine. When CMV-seropositive animals receiving any S protein vaccine (n=6) were compared to CMV-seronegatives (n=7), there was a trend toward decreased reciprocal RBD ELISA titer (p=0.17, Mann-Whitney). However, we noted that IN vaccination was associated with a strikingly lower ELISA titer (640) in a subset of CMV-seropositives.

Conclusion
IN administration of a Pichinde-vectored S vaccine demonstrated equivalent immunogenicity to an adjuvanted protein vaccine in guinea pigs, justifying the continued development of this novel mucosal vaccine strategy. However, pre-existing CMV seropositivity was associated with a trend toward a reduced response. CMV positivity may impact the immune response to S protein subunit vaccines delivered by IN route. Future studies in the guinea pig will focus on transplacental antibody transfer following COVID immunization of pregnant dams. Future clinical studies should examine the role of CMV serostatus both in COVID vaccine response and in disease pathogenesis.