One or two injections of MVA-vectored vaccine shields hACE2 transgenic mice from SARS-CoV-2 upper and lower respiratory tract infection

Abstract

Modified vaccinia virus Ankara (MVA) is a replication-restricted smallpox vaccine, and numerous clinical studies of recombinant MVAs (rMVAs) as vectors for prevention of other infectious diseases, including COVID-19, are in progress. Here, we characterize rMVAs expressing the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Modifications of full-length S individually or in combination included two proline substitutions, mutations of the furin recognition site, and deletion of the endoplasmic retrieval signal. Another rMVA in which the receptor binding domain (RBD) is flanked by the signal peptide and transmembrane domains of S was also constructed. Each modified S protein was displayed on the surface of rMVA-infected cells and was recognized by anti-RBD antibody and soluble hACE2 receptor. Intramuscular injection of mice with the rMVAs induced antibodies, which neutralized a pseudovirus in vitro and, upon passive transfer, protected hACE2 transgenic mice from lethal infection with SARS-CoV-2, as well as S-specific CD3+CD8+IFNγ+ T cells. Antibody boosting occurred following a second rMVA or adjuvanted purified RBD protein. Immunity conferred by a single vaccination of hACE2 mice prevented morbidity and weight loss upon intranasal infection with SARS-CoV-2 3 wk or 7 wk later. One or two rMVA vaccinations also prevented detection of infectious SARS-CoV-2 and subgenomic viral mRNAs in the lungs and greatly reduced induction of cytokine and chemokine mRNAs. A low amount of virus was found in the nasal turbinates of only one of eight rMVA-vaccinated mice on day 2 and none later. Detection of low levels of subgenomic mRNAs in turbinates indicated that replication was aborted in immunized animals.

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA-SARS-2-S in preclinical vaccination

“…Our prime-boost vaccinations with MVA--SARS-2-S did not impair the balanced T helper cell populations monitored in BALB/c mice by spectral flow cytometry. Of note, two additional studies also demonstrated the induction of predominantly TH1-type immune responses in mice immunized with MVA vector vaccines encoding SARS-CoV-2 S antigens (44,45). The importance of vaccine-induced T cell responses is illustrated by studies not only monitoring the adaptive immunity to SARS-CoV-2 in patients, but also demonstrating that strong SARS-CoV-2-specific CD4 + or CD8 + T cell responses are associated with low disease severity in individuals with COVID-19 (5).…”

Why do poxviruses still matter?

“…Recent efforts have focused on using Modified Vaccina virus Ankara to develop vaccines against SARS-CoV-2. These have shown promising effects in mice and macaques [84][85][86][87]. With further research, it is expected that poxvirus vector-based vaccines will be licensed for humans, which requires substantially increasing the investments and efforts to understand the fundamental aspects of poxvirus replication, as well as collaboration among poxvirologists, immunologists, clinicians, and veterinarians.…”

The Mechanisms and Animal Models of SARS-CoV-2 Infection

“…Among them, the lungs of infected mice treated with chloroquine and bafilomycin A1 showed reduced infiltration of inflammatory cells and improved alveolar structure. Liu et al (2021) demonstrated that the recombinant modified vaccinia virus Ankaras (rMVAs) expressing modified forms of SARS-CoV-2 S proteins could not only suppress viral replication in the upper and lower respiratory tracts, but also reduce the expression of cytokines and chemokines in the lungs of hACE2 mice, suggesting that this vaccine had the potential to control COVID-19 during the current pandemic.…”