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16 pages, 2207 KiB

Open AccessArticle

Mutation of Respiratory Syncytial Virus G Protein’s CX3C Motif Attenuates Infection in Cotton Rats and Primary Human Airway Epithelial Cells

by Binh Ha, Tatiana Chirkova, Marina S. Boukhvalova, He Ying Sun, Edward E. Walsh, Christopher S. Anderson, Thomas J. Mariani and Larry J. Anderson

Vaccines 2019, 7(3), 69; https://doi.org/10.3390/vaccines7030069 - 19 Jul 2019

Cited by 15 | Viewed by 3896

Abstract

Despite being a high priority for vaccine development, no vaccine is yet available for respiratory syncytial virus (RSV). A live virus vaccine is the primary type of vaccine being developed for young children. In this report, we describe our studies of infected cotton [...] Read more.

Despite being a high priority for vaccine development, no vaccine is yet available for respiratory syncytial virus (RSV). A live virus vaccine is the primary type of vaccine being developed for young children. In this report, we describe our studies of infected cotton rats and primary human airway epithelial cells (pHAECs) using an RSV r19F with a mutation in the CX3C chemokine motif in the RSV G protein (CX4C). Through this CX3C motif, RSV binds to the corresponding chemokine receptor, CX3CR1, and this binding contributes to RSV infection of pHAECs and virus induced host responses that contribute to disease. In both the cotton rat and pHAECs, the CX4C mutation decreased virus replication and disease and/or host responses to infection. Thus, this mutation, or other mutations that block binding to CX3CR1, has the potential to improve a live attenuated RSV vaccine by attenuating both infection and disease pathogenesis. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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17 pages, 2314 KiB

Open AccessArticle

RSV Vaccine Based on Rhabdoviral Vector Protects after Single Immunization

by Sarah Wilmschen, Sabrina Schneider, Felix Peters, Lea Bayer, Leila Issmail, Zoltán Bánki, Thomas Grunwald, Dorothee von Laer and Janine Kimpel

Vaccines 2019, 7(3), 59; https://doi.org/10.3390/vaccines7030059 - 03 Jul 2019

Cited by 10 | Viewed by 4341

Abstract

The respiratory syncytial virus (RSV) is one major cause of lower respiratory tract infections in childhood and an effective vaccine is still not available. We previously described a new rhabdoviral vector vaccine, VSV-GP, a variant of the vesicular stomatitis virus (VSV), where the [...] Read more.

The respiratory syncytial virus (RSV) is one major cause of lower respiratory tract infections in childhood and an effective vaccine is still not available. We previously described a new rhabdoviral vector vaccine, VSV-GP, a variant of the vesicular stomatitis virus (VSV), where the VSV glycoprotein G is exchanged by the glycoprotein GP of the lymphocytic choriomeningitis virus. Here, we evaluated VSV-GP as vaccine vector for RSV with the aim to induce RSV neutralizing antibodies. Wild-type F (F_wt) or a codon optimized version (F_syn) were introduced at position 5 into the VSV-GP genome. Both F versions were efficiently expressed in VSV-GP-F infected cells and incorporated into VSV-GP particles. In mice, high titers of RSV neutralizing antibodies were induced already after prime and subsequently boosted by a second immunization. After challenge with RSV, viral loads in the lungs of immunized mice were reduced by 2–3 logs with no signs of an enhanced disease induced by the vaccination. Even a single intranasal immunization significantly reduced viral load by a factor of more than 100-fold. RSV neutralizing antibodies were long lasting and mice were still protected when challenged 20 weeks after the boost. Therefore, VSV-GP is a promising candidate for an effective RSV vaccine. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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13 pages, 2829 KiB

Open AccessArticle

Simultaneous Administration of Recombinant Measles Viruses Expressing Respiratory Syncytial Virus Fusion (F) and Nucleo (N) Proteins Induced Humoral and Cellular Immune Responses in Cotton Rats

by Yoshiaki Yamaji, Akihito Sawada, Yosuke Yasui, Takashi Ito and Tetsuo Nakayama

Vaccines 2019, 7(1), 27; https://doi.org/10.3390/vaccines7010027 - 04 Mar 2019

Cited by 5 | Viewed by 3066

Abstract

We previously reported that recombinant measles virus expressing the respiratory syncytial virus (RSV) fusion protein (F), MVAIK/RSV/F, induced neutralizing antibodies against RSV, and those expressing RSV-NP (MVAIK/RSV/NP) and M2-1 (MVAIK/RSV/M2-1) induced RSV-specific CD8⁺/IFN-γ⁺ cells, but not neutralizing antibodies. In the [...] Read more.

We previously reported that recombinant measles virus expressing the respiratory syncytial virus (RSV) fusion protein (F), MVAIK/RSV/F, induced neutralizing antibodies against RSV, and those expressing RSV-NP (MVAIK/RSV/NP) and M2-1 (MVAIK/RSV/M2-1) induced RSV-specific CD8⁺/IFN-γ⁺ cells, but not neutralizing antibodies. In the present study, MVAIK/RSV/F and MVAIK/RSV/NP were simultaneously administered to cotton rats and immune responses and protective effects were compared with MVAIK/RSV/F alone. Sufficient neutralizing antibodies against RSV and RSV-specific CD8⁺/IFN-γ⁺ cells were observed after re-immunization with simultaneous administration. After the RSV challenge, CD8⁺/IFN-γ⁺ increased in spleen cells obtained from the simultaneous immunization group in response to F and NP peptides. Higher numbers of CD8⁺/IFN-γ⁺ and CD4⁺/IFN-γ⁺ cells were detected in lung tissues from the simultaneous immunization group after the RSV challenge. No detectable RSV was recovered from lung homogenates in the immunized groups. Mild inflammatory reactions with the thickening of broncho-epithelial cells and the infiltration of inflammatory cells were observed in lung tissues obtained from cotton rats immunized with MVAIK/RSV/F alone after the RSV challenge. No inflammatory responses were observed after the RSV challenge in the simultaneous immunization groups. The present results indicate that combined administration with MVAIK/RSV/F and MVAIK/RSV/NP induces humoral and cellular immune responses and shows effective protection against RSV, suggesting the importance of cellular immunity. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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17 pages, 3530 KiB

Open AccessArticle

Epitope-Specific Serological Assays for RSV: Conformation Matters

by Emily Phung, Lauren A. Chang, Kaitlyn M. Morabito, Masaru Kanekiyo, Man Chen, Deepika Nair, Azad Kumar, Grace L. Chen, Julie E. Ledgerwood, Barney S. Graham and Tracy J. Ruckwardt

Vaccines 2019, 7(1), 23; https://doi.org/10.3390/vaccines7010023 - 23 Feb 2019

Cited by 24 | Viewed by 6148

Abstract

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in children and older adults. An effective vaccine must elicit neutralizing antibodies targeting the RSV fusion (F) protein, which exists in two major conformations, pre-fusion (pre-F) and post-fusion (post-F). Although 50% of the surface [...] Read more.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in children and older adults. An effective vaccine must elicit neutralizing antibodies targeting the RSV fusion (F) protein, which exists in two major conformations, pre-fusion (pre-F) and post-fusion (post-F). Although 50% of the surface is shared, pre-F contains highly neutralization-sensitive antigenic sites not present on post-F. Recent advancement of several subunit F-based vaccine trials has spurred interest in quantifying and understanding the protective potential of antibodies directed to individual antigenic sites. Monoclonal antibody competition ELISAs are being used to measure these endpoints, but the impact of F conformation and competition from antibodies binding to adjacent antigenic sites has not been thoroughly investigated. Since this information is critical for interpreting clinical trial outcomes and defining serological correlates of protection, we optimized assays to evaluate D25-competing antibodies (DCA) to antigenic site Ø on pre-F, and compared readouts of palivizumab-competing antibodies (PCA) to site II on both pre-F and post-F. We show that antibodies to adjacent antigenic sites can contribute to DCA and PCA readouts, and that cross-competition from non-targeted sites is especially confounding when PCA is measured using a post-F substrate. While measuring DCA and PCA levels may be useful to delineate the role of antibodies targeting the apex and side of the F protein, respectively, the assay limitations and caveats should be considered when conducting immune monitoring during vaccine trials and defining correlates of protection. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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15 pages, 1941 KiB

Open AccessArticle

Development of Luciferase Immunoprecipitation Systems (LIPS) Assay to Detect IgG Antibodies against Human Respiratory Syncytial Virus G-Glycoprotein

by Roberta Lynne Crim, Sangeeta Kumari, Priyanka Jayanti, Susette Audet, Ashwin Kulkarni and Judy Beeler

Vaccines 2019, 7(1), 16; https://doi.org/10.3390/vaccines7010016 - 01 Feb 2019

Cited by 5 | Viewed by 11220

Abstract

Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants and the elderly. Although there is no licensed vaccine, RSV-F and -G glycoproteins are targets for vaccine development and therapeutics. We developed an assay that can detect anti-RSV-G IgG antibodies, either [...] Read more.

Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants and the elderly. Although there is no licensed vaccine, RSV-F and -G glycoproteins are targets for vaccine development and therapeutics. We developed an assay that can detect anti-RSV-G IgG antibodies, either as a biomarker of natural exposure or immunization. RSV genes encoding native and mutated G (mG) proteins from subgroups A and B strains were cloned, expressed as luciferase-tagged proteins, and tested individually to detect anti-RSV-G specific IgG antibodies using a high-throughput luciferase immunoprecipitation system (LIPS-G). RSV monoclonal antibodies and polyclonal antisera specifically bound in the LIPS-G_A and/or -G_B assays; whereas anti-RSV-F and -N, and antisera against measles virus or human metapneumovirus did not bind. Anti-RSV-G_A and -G_B IgG responses detected in mice infected intranasally with RSV-A or -B strains were subtype specific. Subtype specific anti-RSV-G_A or -G_B IgG responses were also detected using paired serum samples from infants while human adolescent serum samples reacted in both LIPS-G_A and -G_B assays, reflecting a broader experience. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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10 pages, 1812 KiB

Open AccessArticle

Neonatal Genetic Delivery of Anti-Respiratory Syncytial Virus (RSV) Antibody by Non-Human Primate-Based Adenoviral Vector to Provide Protection against RSV

by Rika Gomi, Anurag Sharma, Wenzhu Wu and Stefan Worgall

Vaccines 2019, 7(1), 3; https://doi.org/10.3390/vaccines7010003 - 29 Dec 2018

Cited by 6 | Viewed by 3895

Abstract

Respiratory syncytial virus (RSV) is one of the leading causes of lower respiratory tract infection in infants. Immunoprophylaxis with the anti-RSV monoclonal antibody, palivizumab, reduces the risk for RSV-related hospitalizations, but its use is restricted to high-risk infants due to the high costs. [...] Read more.

Respiratory syncytial virus (RSV) is one of the leading causes of lower respiratory tract infection in infants. Immunoprophylaxis with the anti-RSV monoclonal antibody, palivizumab, reduces the risk for RSV-related hospitalizations, but its use is restricted to high-risk infants due to the high costs. In this study, we investigated if genetic delivery of anti-RSV antibody to neonatal mice by chimpanzee adenovirus type 7 expressing the murine form of palivizumab (AdC7αRSV) can provide protection against RSV. Intranasal and intramuscular administration of AdC7αRSV to adult mice resulted in similar levels of anti-RSV IgG in the serum. However, only intranasal administration resulted in detectable levels of anti-RSV IgG in the bronchoalveolar lavage fluid. Intranasal administration of AdC7αRSV provided protection against subsequent RSV challenge. Expression of the anti-RSV antibody was prolonged following intranasal administration of AdC7αRSV to neonatal mice. Protection against RSV was confirmed at 6 weeks of age. These data suggest that neonatal genetic delivery of anti-RSV antibody by AdC7αRSV can provide protection against RSV. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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Review

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14 pages, 538 KiB

Open AccessReview

Will Attention by Vaccine Developers to the Host’s Nuclear Hormone Levels and Immunocompetence Improve Vaccine Success?

by Robert E. Sealy, Bart G. Jones, Sherri L. Surman, Rhiannon R. Penkert, Stephane Pelletier, Geoff Neale and Julia L. Hurwitz

Vaccines 2019, 7(1), 26; https://doi.org/10.3390/vaccines7010026 - 27 Feb 2019

Cited by 14 | Viewed by 3317

Abstract

Despite extraordinary advances in fields of immunology and infectious diseases, vaccine development remains a challenge. The development of a respiratory syncytial virus vaccine, for example, has spanned more than 50 years of research with studies of more than 100 vaccine candidates. Dozens of [...] Read more.

Despite extraordinary advances in fields of immunology and infectious diseases, vaccine development remains a challenge. The development of a respiratory syncytial virus vaccine, for example, has spanned more than 50 years of research with studies of more than 100 vaccine candidates. Dozens of attractive vaccine products have entered clinical trials, but none have completed the path to licensing. Human immunodeficiency virus vaccine development has proven equally difficult, as there is no licensed product after more than 30 years of pre-clinical and clinical research. Here, we examine vaccine development with attention to the host. We discuss how nuclear hormones, including vitamins and sex hormones, can influence responses to vaccines. We show how nuclear hormones interact with regulatory elements of immunoglobulin gene loci and how the deletion of estrogen response elements from gene enhancers will alter patterns of antibody isotype expression. Based on these findings, and findings that nuclear hormone levels are often insufficient or deficient among individuals in both developed and developing countries, we suggest that failed vaccine studies may in some cases reflect weaknesses of the host rather than the product. We encourage analyses of nuclear hormone levels and immunocompetence among study participants in clinical trials to ensure the success of future vaccine programs. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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28 pages, 1155 KiB

Open AccessReview

Utility of the Neonatal Calf Model for Testing Vaccines and Intervention Strategies for Use against Human RSV Infection

by Mariana Guerra-Maupome, Mitchell V. Palmer, Jodi L. McGill and Randy E. Sacco

Vaccines 2019, 7(1), 7; https://doi.org/10.3390/vaccines7010007 - 08 Jan 2019

Cited by 19 | Viewed by 5480

Abstract

Respiratory syncytial virus (RSV) is a significant cause of pediatric respiratory tract infections. It is estimated that two-thirds of infants are infected with RSV during the first year of life and it is one of the leading causes of death in this age [...] Read more.

Respiratory syncytial virus (RSV) is a significant cause of pediatric respiratory tract infections. It is estimated that two-thirds of infants are infected with RSV during the first year of life and it is one of the leading causes of death in this age group worldwide. Similarly, bovine RSV is a primary viral pathogen in cases of pneumonia in young calves and plays a significant role in bovine respiratory disease complex. Importantly, naturally occurring infection of calves with bovine RSV shares many features in common with human RSV infection. Herein, we update our current understanding of RSV infection in cattle, with particular focus on similarities between the calf and human infection, and the recent reports in which the neonatal calf has been employed for the development and testing of vaccines and therapeutics which may be applied to hRSV infection in humans. Full article

(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)

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