Mt10-CVB3 Vaccine Virus Protects against CVB4 Infection by Inducing Cross-Reactive, Antigen-Specific Immune Responses

Group B coxsackieviruses (CVB) containing six serotypes, B1–B6, affect various organs, and multiple serotypes can induce similar diseases such as myocarditis and pancreatitis. Yet, no vaccines are currently available to prevent these infections. Translationally, the derivation of vaccines that offer protection against multiple serotypes is highly desired. In that direction, we recently reported the generation of an attenuated strain of CVB3, termed Mt10, which completely protects against both myocarditis and pancreatitis induced by the homologous wild-type CVB3 strain. Here, we report that the Mt10 vaccine can induce cross-protection against multiple CVB serotypes as demonstrated with CVB4. We note that the Mt10 vaccine could induce cross-reactive neutralizing antibodies (nABs) against both CVB1 and CVB4. In challenge studies with CVB4, the efficacy of the Mt10 vaccine was found to be 92%, as determined by histological evaluation of the heart and pancreas. Antibody responses induced in Mt10/CVB4 challenged animals indicated the persistence of cross-reactive nABs against CVB1, CVB3, and CVB4. Evaluation of antigen-specific immune responses revealed viral protein 1 (VP1)-reactive antibodies, predominantly IgG2a, IgG2b, IgG3, and IgG1. Similarly, by using major histocompatibility complex class II tetramers, we noted induction of VP1-specific CD4 T cells capable of producing multiple T cell cytokines, with interferon-γ being predominant. Finally, none of the vaccine recipients challenged with CVB4 revealed the presence of viral nucleic acid in the heart or pancreas. Taken together, our data suggest that the Mt10 vaccine can prevent infections caused by multiple CVB serotypes, paving the way for the development of monovalent CVB vaccines to prevent heart and pancreatic diseases of enteroviral origin.

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Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2

Journal of Experimental Medicine ◽

10.1084/jem.20020906 ◽

2003 ◽

Vol 197 (6) ◽

pp. 703-709 ◽

Cited By ~ 139

Author(s):

Nancy Wood ◽

Matthew J. Whitters ◽

Bruce A. Jacobson ◽

JoAnn Witek ◽

Joseph P. Sypek ◽

...

Keyword(s):

Immune Responses ◽

Immunoglobulin E ◽

Interferon Γ ◽

Wild Type ◽

Functional Importance ◽

Bone Marrow Macrophage ◽

Tissue Macrophage ◽

High Affinity Receptor ◽

Affinity Receptor ◽

Deficient Mice

Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)α and IL-13Rα1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Rα2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Rα2, mice deficient in IL-13Rα2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Rα2−/− mice despite the fact that serum IL-13 was absent and immune interferon γ production increased compared with wild-type mice. IL-13Rα2–deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Rα2 in regulating immune responses in wild-type mice.

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Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein

Journal of Virology ◽

10.1128/jvi.01176-20 ◽

2020 ◽

Vol 94 (24) ◽

Author(s):

Jung-ah Choi ◽

Junghyun Goo ◽

Eunji Yang ◽

Dae-Im Jung ◽

Sena Lee ◽

...

Keyword(s):

Immune Responses ◽

Recombinant Proteins ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Respiratory Illness ◽

Cross Protection ◽

Effective Vaccine ◽

Wild Type ◽

Boost Vaccination ◽

Cross Neutralization

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness and has a high mortality of ∼34%. However, since its discovery in 2012, an effective vaccine has not been developed for it. To develop a vaccine against multiple strains of MERS-CoV, we targeted spike glycoprotein (S) using prime-boost vaccination with DNA and insect cell-expressed recombinant proteins for the receptor-binding domain (RBD), S1, S2, SΔTM, or SΔER. Our S subunits were generated using an S sequence derived from the MERS-CoV EMC/2012 strain. We examined humoral and cellular immune responses of various combinations with DNA plasmids and recombinant proteins in mice. Mouse sera immunized with SΔER DNA priming/SΔTM protein boosting showed cross-neutralization against 15 variants of S-pseudovirions and the wild-type KOR/KNIH/002 strain. In addition, these immunizations provided full protection against the KOR/KNIH/002 strain challenge in human DPP4 knock-in mice. These findings suggest that vaccination with the S subunits derived from one viral strain can provide cross-protection against variant MERS-CoV strains with mutations in S. DNA priming/protein boosting increased gamma interferon production, while protein-alone immunization did not. The RBD subunit alone was insufficient to induce neutralizing antibodies, suggesting the importance of structural conformation. In conclusion, heterologous DNA priming with protein boosting is an effective way to induce both neutralizing antibodies and cell-mediated immune responses for MERS-CoV vaccine development. This study suggests a strategy for selecting a suitable platform for developing vaccines against MERS-CoV or other emerging coronaviruses. IMPORTANCE Coronavirus is an RNA virus with a higher mutation rate than DNA viruses. Therefore, a mutation in S-protein, which mediates viral infection by binding to a human cellular receptor, is expected to cause difficulties in vaccine development. Given that DNA-protein vaccines promote stronger cell-mediated immune responses than protein-only vaccination, we immunized mice with various combinations of DNA priming and protein boosting using the S-subunit sequences of the MERS-CoV EMC/2012 strain. We demonstrated a cross-protective effect against wild-type KOR/KNIH/002, a strain with two mutations in the S amino acids, including one in its RBD. The vaccine also provided cross-neutralization against 15 different S-pseudotyped viruses. These suggested that a vaccine targeting one variant of S can provide cross-protection against multiple viral strains with mutations in S. The regimen of DNA priming/Protein boosting can be applied to the development of other coronavirus vaccines.

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Circulating SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

10.1101/2021.02.14.21251704 ◽

2021 ◽

Author(s):

Wilfredo F. Garcia-Beltran ◽

Evan C. Lam ◽

Kerri St. Denis ◽

Adam D. Nitido ◽

Zeidy H. Garcia ◽

...

Keyword(s):

Immune Responses ◽

Humoral Immunity ◽

Neutralizing Antibodies ◽

Wild Type ◽

Vaccine Responses ◽

Main Target ◽

Cross Neutralization ◽

Ongoing Surveillance ◽

Multiple Strains ◽

The Impact

SUMMARYVaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of globally circulating variants, we evaluated the neutralization potency of 48 sera from BNT162b2 and mRNA-1273 vaccine recipients against pseudoviruses bearing spike proteins derived from 10 strains of SARS-CoV-2. While multiple strains exhibited vaccine-induced cross-neutralization comparable to wild-type pseudovirus, 5 strains harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was weak and comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic.

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Measles viruses of genotype H1 evade recognition by vaccine-induced neutralizing antibodies targeting the linear haemagglutinin noose epitope

Journal of General Virology ◽

10.1099/vir.0.013524-0 ◽

2009 ◽

Vol 90 (11) ◽

pp. 2739-2745 ◽

Cited By ~ 28

Author(s):

Tim Finsterbusch ◽

Anne Wolbert ◽

Ingrid Deitemeier ◽

Kerstin Meyer ◽

Maria Mar Mosquera ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Measles Virus ◽

Cell Epitope ◽

Vaccine Virus ◽

Wild Type ◽

Live Attenuated Vaccine ◽

B Cell Epitope ◽

Human Sera ◽

Neutralizing Epitopes ◽

Epidemiological Observation

The linear haemagglutinin noose epitope (HNE; aa 379–410) is a protective B-cell epitope and considered to be highly conserved in both the vaccine and the wild-type measles virus (MeV) haemagglutinin (H) proteins. Vaccine virus-derived monoclonal antibodies (mAbs) BH6 and BH216, which target the HNE, neutralized MeVs of genotypes B3, C2, D4, D5, D6, D7 and D8, and the vaccine strain Edmonston Zagreb. In the case of genotype H1, only strain Berlin.DEU/44.01 was neutralized by these mAbs, whereas strains Shenyang.CHN/22.99 and Sofia.BGR/19.05 were not. The H gene sequences of these two strains showed an exchange of proline 397 (P397) to leucine (L397). Mutated H proteins, with P397 exchanged to L and vice versa, were compared with original H proteins by indirect fluorescence assay. H proteins exhibiting P397 but not those with L397 were recognized by BH6 and BH216. This indicates that L397 leads to the loss of the neutralizing HNE. In contrast, human sera obtained from vaccinees (n=10) did not discriminate between genotype H1 variants P397 and L397. This concurs with the epidemiological observation that the live-attenuated vaccine protects against both H1 variants. Furthermore, we demonstrated that MeVs of genotype H1 also lack the neutralizing epitopes defined by the vaccine virus-induced mAbs BH15, BH125 and BH47. The loss of several neutralizing epitopes, as shown for H1 viruses currently circulating endemically in Asia, implies that epitope monitoring should be considered to be included in measles surveillance.

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Difference of hemaglutinins between wild-type and vaccine measles virus in Indonesia

Paediatrica Indonesiana ◽

10.14238/pi48.1.2008.42-8 ◽

2008 ◽

Vol 48 (1) ◽

pp. 42

Author(s):

Made Setiawan ◽

Agus Sjahrurachman ◽

Fera Ibrahim ◽

Agus Suwandono

Keyword(s):

Neutralizing Antibodies ◽

Measles Virus ◽

Vaccine Virus ◽

Amino Acid Sequences ◽

Wild Type Virus ◽

Type Virus ◽

Wild Type ◽

Cell Infection ◽

Aminoacid Sequence ◽

H Protein

Background Hemaglutinin (H) protein of measles virus is veryimportant in the process of host cell infection. H protein is alsoable to induce specific antibodies which can neutralize measlesvirus and block the cell infection.Objective This study aimed to explore the nucleotide and aminoacid sequence differences between wild-type measles virus (G2,G3 and D9) with CAM-70, Schwarz and Edmonston-wt vaccinevirus.Methods The exctration and amplification of the gene wereconducted in the laboratory using biomolecular technology. Thegene and protein analysis were conducted using the bioinformatictechnology.Results The results showed that the differences in nucleotidesequences were highest between wild-type virus and CAM-70vaccine virus (76-77 nucleotides), followed by Schwarz (61-64nucleotides) and Edmonston (60-63 nucleotides). The differencesin amino acid sequences were highest between wild-type virusand CAM-70 (24-29 residues), followed by Schwarz (13-20residues) and Edmonston (12-19 residues).Conclusion The Indonesian wild-type measles virus was geneticallycloser to Schwarz vaccine virus than CAM-70 vaccine virus,hence the neutralizing antibodies generated by Schwarz vaccinewere more specific against Indonesian wild-type virus comparedto CAM-70 vaccine.

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Interdependencies of cellular and humoral immune responses in heterologous and homologous SARS‑CoV‑2 vaccination

10.22541/au.164040480.07315088/v1 ◽

2021 ◽

Author(s):

Luise Erpenbeck ◽

Moritz M. Hollstein ◽

Lennart Münsterkötter ◽

Michael Schön ◽

Armin Bergmann ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Neutralizing Antibodies ◽

Cell Activation ◽

Booster Vaccination ◽

Interferon Γ ◽

T Cell Response ◽

Cellular Immune Responses ◽

Cellular Immune

Background: Homologous and heterologous SARS-CoV-2 vaccinations yield different spike protein-directed humoral and cellular immune responses. This study aimed to explore their currently unknown interdependencies. Methods: COV-ADAPT is a prospective, observational cohort study of 417 healthcare workers who received vaccination with homologous ChAdOx1 nCoV-19, homologous BNT162b2 or with heterologous ChAdOx1 nCoV-19/BNT162b2. We assessed humoral (anti-spike-RBD-IgG, neutralizing antibodies, avidity) and cellular (spike-induced T cell interferon‑γ release) immune responses in blood samples up to 2 weeks before (T1) and 2 to 12 weeks following secondary immunization (T2). Results: Initial vaccination with ChAdOx1 nCoV-19 resulted in lower anti-spike-RBD-IgG compared to BNT162b2 (70±114 vs. 226±279 BAU/ml, p<0.01) at T1. Booster vaccination with BNT162b2 proved superior to ChAdOx1 nCoV-19 at T2 (anti-spike-RBD-IgG: ChAdOx1 nCoV-19/BNT162b2 2387±1627 and homologous BNT162b2 3202±2184 vs. homologous ChAdOx1 nCoV-19 413±461 BAU/ml, both p<0.001; spike-induced T cell interferon-γ release: ChAdOx1 nCoV-19/BNT162b2 5069±6733 and homologous BNT162b2 4880±7570 vs. homologous ChAdOx1 nCoV-19 1152±2243 mIU/ml, both p<0.001). No significant differences were detected between BNT162b2-boostered groups at T2. For ChAdOx1 nCoV-19, no booster effect on T cell activation could be observed. We found associations between anti-spike-RBD-IgG levels (ChAdOx1 nCoV-19/BNT162b2 and homologous BNT162b2) and T cell responses (homologous ChAdOx1 nCoV-19 and ChAdOx1 nCoV-19/BNT162b2) from T1 to T2. Additionally, anti-spike-RBD-IgG and T cell response were linked at both time points (all groups combined). All regimes yielded neutralizing antibodies and increased antibody avidity at T2. Conclusions: Interdependencies between humoral and cellular immune responses differ between common SARS-CoV-2 vaccination regimes. T cell activation is unlikely to compensate for poor humoral responses.

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Persistence of the immune responses and cross-neutralizing activity with Variants of Concern following two doses of adjuvanted SCB-2019 COVID-19 vaccine

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab447 ◽

2021 ◽

Author(s):

Peter C Richmond ◽

Lara Hatchuel ◽

Filippo Pacciarini ◽

Branda Hu ◽

Igor Smolenov ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Phase 1 ◽

Protein S ◽

Competitive Binding ◽

Igg Antibodies ◽

Wild Type ◽

Phase 1 Study ◽

Cross Neutralization ◽

Dose Dependent

Abstract Background We have previously reported the safety and immunogenicity four weeks after two doses of the Clover COVID-19 vaccine candidate, SCB-2019, a stabilized pre-fusion form of the SARS-CoV-2 S-protein (S-trimer). We now report persistence of antibodies up to 6 months after vaccination, and cross-neutralization titers against three Variants of Concern (VoC). Methods In a phase 1 study adult (18–54 years) and elderly (55–75 years) volunteers received two vaccinations 21 days apart with 3, 9 or 30µg doses of SCB-2019 adjuvanted with CpG-1018/alum or placebo. We measured IgG antibodies against SCB-2019, ACE2-competitive-binding antibodies, and neutralizing antibodies against wild type SARS-CoV-2 (Wuhan-Hu-1) at Days 101 and 184, and neutralizing antibodies against three VoC, Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P.1) in Day 36 sera. Results Titers waned from their peak at Days 36–50, but SCB-2019 IgG antibodies, ACE2-competitive binding antibodies and neutralizing antibodies against wild type SARS-CoV-2 persisted at 25–35% of their observed peak levels at Day 184. Day 36 sera also demonstrated dose-dependent increases in neutralizing titers against the three VoC. Conclusions SCB-2019 dose-dependently induced immune responses against wild-type SARS-CoV-2 which persisted up to Day 184. Neutralizing antibodies were cross-reactive against three of the most prevalent VoC.

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Polystyrene nanoparticles induce stronger cellular and more durable humoral immune responses against an inactivated bovine herpesvirus 1 isolate

10.21203/rs.2.24337/v1 ◽

2020 ◽

Author(s):

Xingbo Liu ◽

Zhihao Xin ◽

Fan Zhang ◽

Luyao zhang ◽

Hanyu Yan ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Bovine Herpesvirus ◽

Interferon Γ ◽

Antibody Responses ◽

Live Virus ◽

Herpesvirus Type ◽

Humoral Immune ◽

Development Platform ◽

Humoral Immune Responses

Abstract The inactivated bovine herpesvirus type 1(BoHV-1) vaccines are generally safe and suitable for use in dairy and pregnant cattle, but induces weaker cellular immune responses and shorter antibody responses compared with the modified live virus vaccine. In this study, we used polystyrene (PS) nanoparticles (100 nm) as a carrier for purified inactivated broken BoHV-1 to improve cellular and humoral immune responses compared with the traditional inactivated vaccine. Mice were injected intramuscularly with the inactivated complex mixed with ISA206 adjuvant. Transmission electron microscopy showed that the PS nanoparticles displayed broken BoHV-1 on their surfaces. After validation of BoHV-1 and gB gC gD gE tegument proteins, it proved that the BoHV-conjugated PS nanoparticles induced higher-titer and more durable antibody responses. The inactivated BoHV-PS nanoparticle complex elicited neutralizing antibodies (titer ~2 6 ) in 5 weeks post-immunization in mice. The CD4/CD8 ratio was higher in mice immunized with PS nanoparticles compared with other groups. However, this ratio reached its maximum 1 week later than in mice immunized with ISA206+BoHV-1 or BoHV-1. Levels of interleukin (IL)-4, IL-6, and interferon-γ in followed similar patterns. In conclusion, this pilot study demonstrated that PS nanoparticles can adjuvant inactivated BoHV-1 vaccines, enhancing both cell-mediated immune responses and the duration of antibody responses. This study provides the foundation for a new development platform for inactivated vaccines, which can elicit potent cellular and humoral immune responses in animals and humans.The inactivated bovine herpesvirus type 1(BoHV-1) vaccines are generally safe and suitable for use in dairy and pregnant cattle, but induces weaker cellular immune responses and shorter antibody responses compared with the modified live virus vaccine. In this study, we used polystyrene (PS) nanoparticles (100 nm) as a carrier for purified inactivated broken BoHV-1 to improve cellular and humoral immune responses compared with the traditional inactivated vaccine. Mice were injected intramuscularly with the inactivated complex mixed with ISA206 adjuvant. Transmission electron microscopy showed that the PS nanoparticles displayed broken BoHV-1 on their surfaces. After validation of BoHV-1 and gB gC gD gE tegument proteins, it proved that the BoHV-conjugated PS nanoparticles induced higher-titer and more durable antibody responses. The inactivated BoHV-PS nanoparticle complex elicited neutralizing antibodies (titer ~2 6 ) in 5 weeks post-immunization in mice. The CD4/CD8 ratio was higher in mice immunized with PS nanoparticles compared with other groups. However, this ratio reached its maximum 1 week later than in mice immunized with ISA206+BoHV-1 or BoHV-1. Levels of interleukin (IL)-4, IL-6, and interferon-γ in followed similar patterns. In conclusion, this pilot study demonstrated that PS nanoparticles can adjuvant inactivated BoHV-1 vaccines, enhancing both cell-mediated immune responses and the duration of antibody responses. This study provides the foundation for a new development platform for inactivated vaccines, which can elicit potent cellular and humoral immune responses in animals and humans.

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CD2 Regulates the Positive Selection and Function of Antigen-Specific CD4−CD8+ T Cells

Blood ◽

10.1182/blood.v89.4.1308 ◽

1997 ◽

Vol 89 (4) ◽

pp. 1308-1318 ◽

Cited By ~ 53

Author(s):

Soo-Jeet Teh ◽

Nigel Killeen ◽

Alexander Tarakhovsky ◽

Dan R. Littman ◽

Hung-Sia Teh

Keyword(s):

T Cell ◽

Immune Responses ◽

Positive Selection ◽

Cell Receptor ◽

Selective Advantage ◽

Interferon Γ ◽

Histocompatibility Complex ◽

T Cell Immune Responses ◽

And Function ◽

Selection Of

Abstract The CD2 glycoprotein has been implicated in both positive and negative regulation of T-cell mitogenesis. To study the involvement of CD2 in T-lymphocyte development and immune responses, we have analyzed two lines of CD2-null mice, each expressing a distinct class I major histocompatibility complex (MHC)-restricted T-cell receptor (TCR). In both situations, the absence of CD2 appeared to promote the positive selection of cells in a manner that is similar to that which occurs in the absence of CD5. Consistent with this, compound homozygotes that lacked both CD2 and CD5 showed evidence of enhanced positive selection even in the absence of a transgenic TCR. Despite the observed enhancement of positive selection, the lack of CD2 was associated with defects in proliferative responses and interferon-γ production when transgenic thymocytes and mature T lymphocytes were stimulated with the appropriate antigens. These findings raise the possibility that impaired sensitivity to selecting ligands in the thymus may provide a selective advantage that improves the efficiency of positive selection for certain TCRs. Furthermore, the results highlight the potential for a differential role for CD2 in thymocyte selection and T-cell immune responses.

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A Live Attenuated H7N7 Candidate Vaccine Virus Induces Neutralizing Antibody That Confers Protection from Challenge in Mice, Ferrets, and Monkeys

Journal of Virology ◽

10.1128/jvi.01305-10 ◽

2010 ◽

Vol 84 (22) ◽

pp. 11950-11960 ◽

Cited By ~ 40

Author(s):

Ji-Young Min ◽

Leatrice Vogel ◽

Yumiko Matsuoka ◽

Bin Lu ◽

David Swayne ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Reverse Genetics ◽

Neutralizing Antibody ◽

Vaccine Virus ◽

Candidate Vaccine ◽

Temperature Sensitive ◽

Wild Type ◽

Phase I Clinical Trials ◽

Lethal Challenge ◽

Challenge Virus

ABSTRACT A live attenuated H7N7 candidate vaccine virus was generated by reverse genetics using the modified hemagglutinin (HA) and neuraminidase (NA) genes of highly pathogenic (HP) A/Netherlands/219/03 (NL/03) (H7N7) wild-type (wt) virus and the six internal protein genes of the cold-adapted (ca) A/Ann Arbor/6/60 ca (AA ca) (H2N2) virus. The reassortant H7N7 NL/03 ca vaccine virus was temperature sensitive and attenuated in mice, ferrets, and African green monkeys (AGMs). Intranasal (i.n.) administration of a single dose of the H7N7 NL/03 ca vaccine virus fully protected mice from lethal challenge with homologous and heterologous H7 viruses from Eurasian and North American lineages. Two doses of the H7N7 NL/03 ca vaccine induced neutralizing antibodies in serum and provided complete protection from pulmonary replication of homologous and heterologous wild-type H7 challenge viruses in mice and ferrets. One dose of the H7N7 NL/03 ca vaccine elicited an antibody response in one of three AGMs that was completely protected from pulmonary replication of the homologous wild-type H7 challenge virus. The contribution of CD8+ and/or CD4+ T cells to the vaccine-induced protection of mice was evaluated by T-cell depletion; T lymphocytes were not essential for the vaccine-induced protection from lethal challenge with H7 wt viruses. Additionally, passively transferred neutralizing antibody induced by the H7N7 NL/03 ca virus protected mice from lethality following challenge with H7 wt viruses. The safety, immunogenicity, and efficacy of the H7N7 NL/03 ca vaccine virus in mice, ferrets, and AGMs support the evaluation of this vaccine virus in phase I clinical trials.

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