scholarly journals HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

2019 ◽  
Author(s):  
Cody S. Nelson ◽  
Jennifer A. Jenks ◽  
Norbert Pardi ◽  
Matthew Goodwin ◽  
Hunter Roark ◽  
...  
Keyword(s):  
Protein Structure ◽  
Human Cytomegalovirus ◽  
Neutralizing Antibody ◽  
The United States ◽  
Antibody Responses ◽  
Full Length ◽  
Glycoprotein B ◽  
Transplant Recipients ◽  
Igg Binding ◽  
Infant Birth

AbstractA vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy is a primary strategy to reduce the incidence of congenital disease. Similarly, vaccination of transplant recipients against HCMV has been proposed to prevent transplant-associated HCMV morbidity. The MF59-adjuvanted glycoprotein B protein subunit vaccine (gB/MF59) is the most efficacious tested to-date for both indications. We previously identified that gB/MF59 vaccination elicited poor neutralizing antibody responses and an immunodominant response against gB antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White rabbits were administered 3 sequential doses of full-length gB protein with an MF59-like squalene adjuvant (analogous to clinically-tested vaccine), gB ectodomain protein (lacking AD-3) with squalene adjuvant, or lipid nanoparticle (LNP)-packaged nucleoside-modified mRNA encoding full-length gB. The AD-3 immunodominant IgG response following human gB/MF59 vaccination was closely mimicked in rabbits, with 78% of binding antibodies directed against this region in the full-length gB protein group compared to 1% and 46% in the ectodomain and mRNA-LNP-vaccinated groups, respectively. All vaccines were highly immunogenic with similar kinetics and comparable peak gB-binding and functional antibody responses. Although gB ectodomain subunit vaccination reduced targeting of non-neutralizing epitope AD-3, it did not improve vaccine-elicited neutralizing or non-neutralizing antibody functions. gB nucleoside-modified mRNA-LNP-immunized rabbits exhibited enhanced durability of IgG binding to soluble and cell membrane-associated gB protein as well as HCMV-neutralizing function. Furthermore, the gB mRNA-LNP vaccine enhanced breadth of IgG binding responses against discrete gB peptide residues. Finally, low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-LNP vaccine groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest that the gB mRNA-LNP vaccine candidate, aiming to improve upon the partial efficacy of gB/MF59 vaccination, should be further evaluated in preclinical models.Author summaryHuman cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, resulting in permanent neurologic disability for one newborn child every hour in the United States. Furthermore, this virus causes significant morbidity and mortality in immune-suppressed transplant recipients. After more than a half century of research and development, we remain without a clinically-licensed vaccine or therapeutic to reduce the burden of HCMV-associated disease. In this study, we sought to improve upon the glycoprotein B protein vaccine (gB/MF59), the most efficacious HCMV vaccine evaluated in clinical trial, via targeted modifications to either the protein structure or vaccine formulation. An attempt to alter the protein structure to focus the immune response on vulnerable epitopes (‘gB ectodomain’) had little effect on the quality or function of the vaccine-elicited antibodies. However, a novel vaccine platform, nucleoside-modified mRNA formulated in lipid nanoparticles, increased the durability and breadth of vaccine-elicited immune responses. We propose that an mRNA-based gB vaccine may ultimately prove more efficacious than the gB/MF59 vaccine and should be further evaluated for its ability to elicit antiviral immune factors that can prevent both infant and transplant-associated disease caused by HCMV infection.

scholarly journals Human Cytomegalovirus Glycoprotein B Nucleoside-Modified mRNA Vaccine Elicits Antibody Responses with Greater Durability and Breadth than MF59-Adjuvanted gB Protein Immunization

2020 ◽  
Vol 94 (9) ◽  
Author(s):  
Cody S. Nelson ◽  
Jennifer A. Jenks ◽  
Norbert Pardi ◽  
Matthew Goodwin ◽  
Hunter Roark ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Cell Activity ◽  
The United States ◽  
Antibody Responses ◽  
Full Length ◽  
Glycoprotein B ◽  
Protein Vaccine ◽  
Protein Subunit ◽  
Vaccine Platform ◽  
Infant Birth

ABSTRACT A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy is a primary strategy to reduce the incidence of congenital disease. The MF59-adjuvanted glycoprotein B (gB) protein subunit vaccine (gB/MF59) is the most efficacious vaccine tested to date for this indication. We previously identified that gB/MF59 vaccination elicited poor neutralizing antibody responses and an immunodominant response against gB antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White rabbits were administered 3 sequential doses of the full-length gB protein with an MF59-like squalene-based adjuvant, the gB ectodomain protein (lacking AD-3) with squalene adjuvant, or lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA encoding full-length gB. All vaccines were highly immunogenic with similar kinetics and comparable peak gB-binding and functional antibody responses. The AD-3-immunodominant IgG response following human gB/MF59 vaccination was closely mimicked in rabbits. Though gB ectodomain subunit vaccination eliminated targeting of epitopes in AD-3, it did not improve vaccine-elicited neutralizing or nonneutralizing antibody functions. gB nucleoside-modified mRNA-LNP-immunized rabbits exhibited an enhanced durability of vaccine-elicited antibody responses. Furthermore, the gB mRNA-LNP vaccine enhanced the breadth of IgG binding responses against discrete gB peptides. Finally, low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-LNP groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest that the use of gB nucleoside-modified mRNA-LNP vaccines is a viable strategy for improving on the partial efficacy of gB/MF59 vaccination and should be further evaluated in preclinical models. IMPORTANCE Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, resulting in permanent neurological disability for one newborn child every hour in the United States. After more than a half century of research and development, we remain without a clinically licensed vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease. In this study, we sought to improve upon the glycoprotein B protein vaccine (gB/MF59), the most efficacious HCMV vaccine evaluated in a clinical trial, via targeted modifications to either the protein structure or vaccine formulation. Utilization of a novel vaccine platform, nucleoside-modified mRNA formulated in lipid nanoparticles, increased the durability and breadth of vaccine-elicited antibody responses. We propose that an mRNA-based gB vaccine may ultimately prove more efficacious than the gB/MF59 vaccine and should be further evaluated for its ability to elicit antiviral immune factors that can prevent HCMV-associated disease.

scholarly journals Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection

2021 ◽  
Author(s):  
Eleanor C. Semmes ◽  
Itzayana G. Miller ◽  
Jennifer A. Jenks ◽  
Courtney E. Wimberly ◽  
Stella J. Berendam ◽  
...  
Keyword(s):  
Cord Blood ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Passive Immunization ◽  
Congenital Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
High Avidity ◽  
Igg Binding ◽  
Congenital Hcmv Infection

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital infection has been hindered by limited knowledge of the immune responses that protect against placental HCMV transmission in maternal primary and nonprimary infection. To identify protective antibody responses, we measured anti-HCMV IgG binding and anti-viral functions in maternal and cord blood sera from HCMV transmitting (n=41) and non- transmitting (n=40) mother-infant dyads identified via a large U.S.-based public cord blood bank. In a predefined immune correlate analysis, maternal monocyte-mediated antibody-dependent cellular phagocytosis (ADCP) and high avidity IgG binding to HCMV envelope glycoproteins were associated with decreased risk of congenital HCMV infection. Moreover, HCMV-specific IgG engagement of FcγRI and FcγRIIA, which mediate non-neutralizing antibody responses, was enhanced in non-transmitting mother-infant dyads and strongly correlated with ADCP. These findings suggest that Fc effector functions including ADCP protect against placental HCMV transmission. Taken together, our data indicate that future active and passive immunization strategies to prevent congenital HCMV infection should target Fc-mediated non-neutralizing antibody responses.

scholarly journals HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

2018 ◽  
Author(s):  
Cody S. Nelson ◽  
Tori Huffman ◽  
Eduardo Cisneros de la Rosa ◽  
Guanhua Xie ◽  
Nathan Vandergrift ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Vaccine Efficacy ◽  
Subunit Vaccine ◽  
Hcmv Infection ◽  
Neutralizing Antibody ◽  
The United States ◽  
Glycoprotein B ◽  
Vaccine Platform ◽  
Effector Functions ◽  
Epitope Specificity

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to-date, demonstrating approximately 50% efficacy in preventing HCMV acquisition in phase II trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and non-neutralizing anti-HCMV effector functions, and compared to an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and Domain I. Interestingly, vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this non-neutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound trimeric, membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, though were poor mediators of NK cell activation. Altogether, these data suggest that non-neutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.SignificanceThe CDC estimates that every hour, a child is born in the United States with permanent neurologic disability resulting from human cytomegalovirus (HCMV) infection – more than is caused by Down syndrome, fetal alcohol syndrome, and neural tube defects combined. A maternal vaccine to block transmission of HCMV to the developing fetus is a necessary intervention to prevent these adverse outcomes. The gB/MF59 vaccine is the most successful tested clinically to-date, achieving 50% reduction in HCMV acquisition. This manuscript establishes the function and epitope specificity of the humoral response stimulated by this vaccine that may explain the partial vaccine efficacy. Understanding the mechanism of gB/MF59-elicited protective immune responses will guide rational design and evaluation of the next generation of HCMV vaccines.

scholarly journals Intrahost Dynamics of Human Cytomegalovirus Variants Acquired by Seronegative Glycoprotein B Vaccinees

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Cody S. Nelson ◽  
Diana Vera Cruz ◽  
Melody Su ◽  
Guanhua Xie ◽  
Nathan Vandergrift ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Rational Design ◽  
Hcmv Infection ◽  
Vaccine Trial ◽  
The United States ◽  
Glycoprotein B ◽  
Viral Population ◽  
Vaginal Fluid ◽  
The Impact ◽  
Placebo Recipients

ABSTRACTHuman cytomegalovirus (HCMV) is the most common congenital infection worldwide and a frequent cause of hearing loss and debilitating neurologic disease in newborn infants. Thus, a vaccine to prevent HCMV-associated congenital disease is a public health priority. One potential strategy is vaccination of women of child bearing age to prevent maternal HCMV acquisition during pregnancy. The glycoprotein B (gB) plus MF59 adjuvant subunit vaccine is the most efficacious tested clinically to date, demonstrating 50% protection against primary HCMV infection in a phase 2 clinical trial. Yet, the impact of gB/MF59-elicited immune responses on the population of viruses acquired by trial participants has not been assessed. In this analysis, we employed quantitative PCR as well as multiple sequencing methodologies to interrogate the magnitude and genetic composition of HCMV populations infecting gB/MF59 vaccinees and placebo recipients. We identified several differences between the viral dynamics in acutely infected vaccinees and placebo recipients. First, viral load was reduced in the saliva of gB vaccinees, though not in whole blood, vaginal fluid, or urine. Additionally, we observed possible anatomic compartmentalization of gB variants in the majority of vaccinees compared to only a single placebo recipient. Finally, we observed reduced acquisition of genetically related gB1, gB2, and gB4 genotype “supergroup” HCMV variants among vaccine recipients, suggesting that the gB1 genotype vaccine construct may have elicited partial protection against HCMV viruses with antigenically similar gB sequences. These findings suggest that gB immunization had a measurable impact on viral intrahost population dynamics and support future analysis of a larger cohort.IMPORTANCEThough not a household name like Zika virus, human cytomegalovirus (HCMV) causes permanent neurologic disability in one newborn child every hour in the United States, which is more than that for Down syndrome, fetal alcohol syndrome, and neural tube defects combined. There are currently no established effective measures to prevent viral transmission to the infant following HCMV infection of a pregnant mother. However, the glycoprotein B (gB)/MF59 vaccine, which aims to prevent pregnant women from acquiring HCMV, is the most successful HCMV vaccine tested clinically to date. Here, we used viral DNA isolated from patients enrolled in a gB vaccine trial who acquired HCMV and identified several impacts that this vaccine had on the size, distribution, and composition of thein vivoviral population. These results have increased our understanding of why the gB/MF59 vaccine was partially efficacious, and such investigations will inform future rational design of a vaccine to prevent congenital HCMV.

scholarly journals Specificity and effector functions of non-neutralizing gB-specific monoclonal antibodies isolated from healthy individuals with human cytomegalovirus infection

2020 ◽  
Author(s):  
Matthew L. Goodwin ◽  
Helen S. Webster ◽  
Hsuan-Yuan Wang ◽  
Jennifer A. Jenks ◽  
Cody S. Nelson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Effector Cell ◽  
Natural Infection ◽  
Congenital Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Domain Specificity ◽  
Cell Functions ◽  
The Impact

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection, and the leading nongenetic cause of sensorineural hearing loss (SNHL) in newborns globally. A gB subunit vaccine administered with adjuvent MF59 (gB/MF59) is the most efficacious tested to-date, achieving 50% efficacy in preventing infection of HCMV-seronegative mothers. We recently discovered that gB/MF59 vaccination elicited primarily non-neutralizing antibody responses, that HCMV strains acquired by vaccinees more often included strains with gB genotypes that are distinct from the vaccine antigen, and that protection against HCMV acquisition correlated with ability of vaccine-elicited antibodies to bind to membrane associated gB. Thus, we hypothesized that gB-specific non-neutralizing antibody binding breadth and function are dependent on their epitope and genotype specificity as well as their ability to interact with membrane-associated gB. Twenty-four gB-specific monoclonal antibodies (mAbs) isolated from naturally HCMV-infected individuals were mapped for gB domain specificity by binding antibody multiplex assay (BAMA) and for genotype preference binding to membrane-associated gB presented on transfected cells. We defined their non-neutralizing functions including antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC). The isolated gB-specific non-neutralizing mAbs were primarily specific for Domain II and linear antigenic domain 2 site 2 (AD2). We observed variability in mAb gB genotype binding preference, with increased binding to gB genotypes 2 and 4. Functional studies identified two gB-specific mAbs that facilitate ADCP and have binding specificities of AD2 and Domain II. This investigation provides novel understanding on the impact of gB domain specificity and antigenic variability on gB-specific non-neutralizing antibody responses.ImportanceHCMV is the most common congenital infection worldwide, but development of a successful vaccine remains elusive. gB-specific non-neutralizing mAbs, represent a distinct anti-HCMV Ab subset implicated in the protection against primary infection during numerous phase-II gB/MF59 vaccine trials. By studying non-neutralizing gB-specific mAbs from naturally infected individuals, this study provides novel characterization of binding site specificity, genotypic preference, and effector cell functions mediated by mAbs elicited in natural infection. We found that a panel of twenty-four gB-specific non-neutralizing mAbs bind across multiple regions of the gB protein, traditionally through to be targeted by neutralizing mAbs only, and bind differently to gB depending if the protein is soluble versus embedded in a membrane. This investigation provides novel insight into the gB-specific binding characteristics and effector cell functions mediated by non-neutralizing gB-specific mAbs elicited through natural infection, providing new endpoints for future vaccine development.

scholarly journals Antibody responses to rhesus cytomegalovirus glycoprotein B in naturally infected rhesus macaques

2003 ◽  
Vol 84 (12) ◽  
pp. 3371-3379 ◽  
Author(s):  
Yujuan Yue ◽  
Shan Shan Zhou ◽  
Peter A. Barry
Keyword(s):  
Specific Antibody ◽  
Transmembrane Domain ◽  
Solid Phase ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Full Length ◽  
Glycoprotein B ◽  
Primate Model ◽  
Specific Antibodies ◽  
Rhesus Cytomegalovirus

Rhesus cytomegalovirus (RhCMV) exhibits strong parallels with human CMV (HCMV) in terms of nucleic and amino acid identities, natural history, and mechanisms of persistence and pathogenesis in its natural host, rhesus macaques (Macaca mulatta). To determine whether this non-human primate model would be useful to assess vaccine strategies for HCMV, host immune responses to RhCMV glycoprotein B (gB) were evaluated in RhCMV-infected monkeys. Total protein extracts were prepared from cells transiently transfected with an expression plasmid for either the full-length gB or a derivative (gBΔ, 1–680 aa) lacking both the transmembrane domain and cytoplasmic tail. Western blot analysis showed identical reactivity of macaque sera with full-length gB and its derivative gBΔ, indicating that the immunodominant epitopes of gB are contained in the extracellular portion of the protein. Using gBΔ extract as a solid phase, a sensitive and specific ELISA was established to characterize gB antibody responses in monkeys acutely and chronically infected with RhCMV. During primary infection (seroconversion), gB-specific antibodies developed concurrently and in parallel with total RhCMV-specific antibodies. However, during chronic infection gB-specific antibody responses were variable. A strong correlation was observed between neutralizing and gB-specific antibody levels in RhCMV-seropositive monkeys. Taken together, the results of this study indicate that, similar to host humoral responses to HCMV gB, anti-gB antibodies are an integral part of humoral immunity to RhCMV infection and probably play an important protective role in limiting the extent of RhCMV infection. Thus, the rhesus macaque model of HCMV infection is relevant for testing gB-based immune therapies.

scholarly journals Genetic signatures of human cytomegalovirus variants acquired by seronegative glycoprotein B vaccinees

2018 ◽  
Author(s):  
Cody S. Nelson ◽  
Diana Vera Cruz ◽  
Melody Su ◽  
Guanhua Xie ◽  
Nathan Vandergrift ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Rational Design ◽  
Hcmv Infection ◽  
Vaccine Trial ◽  
The United States ◽  
Glycoprotein B ◽  
Viral Population ◽  
The Impact ◽  
Placebo Recipients

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection worldwide, and a frequent cause of hearing loss or debilitating neurologic disease in newborn infants. Thus, a vaccine to prevent HCMV-associated congenital disease is a public health priority. One potential strategy is vaccination of women of child-bearing age to prevent maternal HCMV acquisition during pregnancy. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine is the most efficacious tested clinically to date, demonstrating approximately 50% protection against HCMV infection of seronegative women in multiple phase 2 trials. Yet, the impact of gB/MF59-elicited immune responses on the population of viruses acquired by trial participants has not been assessed. In this analysis, we employed quantitative PCR as well as multiple sequencing methodologies to interrogate the magnitude and genetic composition of HCMV populations infecting gB/MF59 vaccinees and placebo recipients. We identified several differences between the viral dynamics of acutely-infected vaccinees and placebo recipients. First, there was reduced magnitude viral shedding in the saliva of gB vaccinees. Additionally, employing a panel of tests for genetic compartmentalization, we noted tissue-specific gB haplotypes in the majority of vaccinees though only in a single placebo recipient. Finally, we observed reduced acquisition of genetically-related gB1, gB2, and gB4 genotype “supergroup” HCMV variants among vaccine recipients, suggesting that the gB1 genotype vaccine construct may have elicited partial protection against HCMV viruses with antigenically-similar gB sequences. These findings indicate that gB immunization may have had a measurable impact on viral intrahost population dynamics and support future analysis of a larger cohort.Author SummaryThough not a household name like Zika virus, human cytomegalovirus (HCMV) causes permanent neurologic disability in one newborn child every hour in the United States - more than Down syndrome, fetal alcohol syndrome, and neural tube defects combined. There are currently no established effective preventative measures to inhibit congenital HCMV transmission following acute or chronic HCMV infection of a pregnant mother. However, the glycoprotein B (gB) vaccine is the most effective HCMV vaccine tried clinically to date. Here, we utilized high-throughput, next-generation sequencing of viral DNA isolated from patients enrolled in a gB vaccine trial, and identified several impacts that this vaccine had on the size, distribution, and composition of thein vivoviral population. These results have increased our understanding of why the gB/MF59 vaccine was partially efficacious and will inform future rational design of a vaccine to prevent congenital HCMV.

scholarly journals Modified Vaccinia Ankara Based SARS-CoV-2 Vaccine Expressing Full-Length Spike Induces Strong Neutralizing Antibody Response

2020 ◽  
Author(s):  
Nanda Kishore Routhu ◽  
Sailaja Gangadhara ◽  
Narayanaiah Cheedarla ◽  
Ayalnesh Shiferaw ◽  
Sheikh Abdul Rahman ◽  
...  
Keyword(s):  
Antibody Response ◽  
Room Temperature ◽  
Vaccine Candidate ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Full Length ◽  
Spike Protein ◽  
Strongly Correlated ◽  
Igg Antibodies ◽  
Potential Vaccine

AbstractThere is a great need for the development of vaccines for preventing SARS-CoV-2 infection and mitigating the COVID-19 pandemic. Here, we developed two modified vaccinia Ankara (MVA) based vaccines which express either a membrane anchored full-length spike protein (MVA/S) stabilized in a prefusion state or the S1 region of the spike (MVA/S1) which forms trimers and is secreted. Both immunogens contained the receptor-binding domain (RBD) which is a known target of antibody-mediated neutralization. Following immunizations with MVA/S or MVA/S1, both spike protein recombinants induced strong IgG antibodies to purified full-length SARS-CoV-2 spike protein. The MVA/S induced a robust antibody response to purified RBD, S1 and S2 whereas MVA/S1 induced an antibody response to the S1 region outside of the RBD region. Both vaccines induced an antibody response in the lung and that was associated with induction of bronchus-associated lymphoid tissue. MVA/S but not MVA/S1 vaccinated mice generated robust neutralizing antibody responses against SARS-CoV-2 that strongly correlated with RBD antibody binding titers. Mechanistically, S1 binding to ACE-2 was strong but reduced following prolonged pre-incubation at room temperature suggesting confirmation changes in RBD with time. These results demonstrate MVA/S is a potential vaccine candidate against SARS-CoV-2 infection.

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