Priorities for developing respiratory syncytial virus vaccines in different target populations

The development of an effective vaccine against respiratory syncytial virus (RSV) has been hampered by major difficulties that occurred in the 1960s when a formalin-inactivated vaccine led to increased severity of RSV disease after acquisition of the virus in the RSV season after vaccination. Recent renewed efforts to develop a vaccine have resulted in about 38 candidate vaccines and monoclonal antibodies now in clinical development. The target populations for effective vaccination are varied and include neonates, young children, pregnant women, and older adults. The reasons for susceptibility to infection in each of these groups may be different and, therefore, could require different vaccine types for induction of protective immune responses, adding a further challenge for vaccine development. Here, we review the current knowledge of RSV vaccine development for these target populations and propose a view and rationale for prioritizing RSV vaccine development.

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Progress toward a Respiratory Syncytial Virus Vaccine

Clinical and Vaccine Immunology ◽

10.1128/cvi.00037-16 ◽

2016 ◽

Vol 23 (3) ◽

pp. 186-188 ◽

Cited By ~ 48

Author(s):

Kathleen M. Neuzil

Keyword(s):

Viral Load ◽

Respiratory Syncytial Virus ◽

Virus Vaccine ◽

Effective Vaccine ◽

Vaccine Candidates ◽

Target Populations ◽

Link Type ◽

History Of ◽

Syncytial Virus ◽

Respiratory Syncytial Virus Vaccine

ABSTRACTIn accompanying papers (P. L. Acosta, M. T. Caballero, and F. P. Polack, Clin Vaccine Immunol 23:189–195, 2016,http://dx.doi.org/10.1128/CVI.00609-15; M. Vissers, I. M. L. Ahout, M. I. de Jonge, and G. Ferwerda, Clin Vaccine Immunol 23:243–245, 2016,http://dx.doi.org/10.1128/CVI.00590-15) in this issue ofClinical and Vaccine Immunology, the history of and immune mechanisms underlying vaccine-enhanced respiratory syncytial virus (RSV) disease and of investigations of mucosal antibodies and their association with viral load in RSV-infected children, respectively, are described. This commentary discusses RSV vaccine candidates, target populations, and the challenges associated with achieving a safe and effective vaccine.

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Single Immunization of a Vaccine Vectored by a Novel Recombinant Vaccinia Virus Affords Effective Protection Against Respiratory Syncytial Virus Infection in Cotton Rats

Frontiers in Immunology ◽

10.3389/fimmu.2021.747866 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marsha S. Russell ◽

Sathya N. Thulasi Raman ◽

Caroline Gravel ◽

Wanyue Zhang ◽

Annabelle Pfeifle ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Vaccinia Virus ◽

High Efficiency ◽

Vaccine Development ◽

Nasal Administration ◽

Effective Vaccine ◽

High Dose ◽

Cotton Rats ◽

Syncytial Virus ◽

Vectored Vaccine

Respiratory syncytial virus (RSV) is a leading cause of respiratory infections worldwide and disease management measures are hampered by the lack of a safe and effective vaccine against the infection. We constructed a novel recombinant RSV vaccine candidate based on a deletion mutant vaccinia virus platform, in that the host range genes E3L and K3L were deleted (designated as VACVΔE3LΔK3L) and a poxvirus K3L ortholog gene was used as a marker for the rapid and efficient selection of recombinant viruses. The safety of the modified vaccinia virus was investigated by intranasal administration of BALB/c mice with the modified vaccinia vector using a dose known to be lethal in the wild-type Western Reserve. Only a minor loss of body weight by less than 5% and mild pulmonary inflammation were observed, both of which were transient in nature following nasal administration of the high-dose modified vaccinia virus. In addition, the viruses were cleared from the lung in 2 days with no viral invasions of the brain and other vital organs. These results suggest that the virulence of the virus has been essentially abolished. We then investigated the efficiency of the vector for the delivery of vaccines against RSV through comparison with another RSV vaccine delivered by the widely used Modified Vaccinia virus Ankara (MVA) backbone. In the cotton rats, we found a single intramuscular administration of VACVΔE3LΔK3L-vectored vaccine elicited immune responses and protection at a level comparable to the MVA-vectored vaccine against RSV infection. The distinct features of this novel VACV vector, such as an E3L deletion for attenuation and a K3L ortholog for positive selection and high efficiency for vaccine delivery, could provide unique advantages to the application of VACV as a platform for vaccine development.

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Contribution of Dendritic Cells in Protective Immunity against Respiratory Syncytial Virus Infection

Viruses ◽

10.3390/v12010102 ◽

2020 ◽

Vol 12 (1) ◽

pp. 102 ◽

Cited By ~ 2

Author(s):

Hi Eun Jung ◽

Tae Hoon Kim ◽

Heung Kyu Lee

Keyword(s):

Dendritic Cells ◽

Respiratory Syncytial Virus ◽

Immune Responses ◽

Defense Mechanisms ◽

Adaptive Immune Response ◽

The Elderly ◽

Effective Vaccine ◽

Adaptive Immune ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. The socioeconomic burden of RSV infection is substantial because it leads to serious respiratory problems, subsequent hospitalization, and mortality. Despite its clinical significance, a safe and effective vaccine is not yet available to prevent RSV infection. Upon RSV infection, lung dendritic cells (DCs) detecting pathogens migrate to the lymph nodes and activate the adaptive immune response. Therefore, RSV has evolved various immunomodulatory strategies to inhibit DC function. Due to the capacity of RSV to modulate defense mechanisms in hosts, RSV infection results in inappropriate activation of immune responses resulting in immunopathology and frequent reinfection throughout life. This review discusses how DCs recognize invading RSV and induce adaptive immune responses, as well as the regulatory mechanisms mediated by RSV to disrupt DC functions and ultimately avoid host defenses.

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Comparison of Immune Responses to Different Versions of VLP Associated Stabilized RSV Pre-Fusion F Protein

Vaccines ◽

10.3390/vaccines7010021 ◽

2019 ◽

Vol 7 (1) ◽

pp. 21 ◽

Cited By ~ 4

Author(s):

Lori Cullen ◽

Madelyn Schmidt ◽

Gretel Torres ◽

Adam Capoferri ◽

Trudy Morrison

Keyword(s):

Monoclonal Antibodies ◽

Respiratory Syncytial Virus ◽

Immune Responses ◽

Fusion Protein ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Vaccine Candidates ◽

F Protein ◽

Syncytial Virus ◽

Conformation Stability

Efforts to develop a vaccine for respiratory syncytial virus (RSV) have primarily focused on the RSV fusion protein. The pre-fusion conformation of this protein induces the most potent neutralizing antibodies and is the focus of recent efforts in vaccine development. Following the first identification of mutations in the RSV F protein (DS-Cav1 mutant protein) that stabilized the pre-fusion conformation, other mutant stabilized pre-fusion F proteins have been described. To determine if there are differences in alternate versions of stabilized pre-fusion F proteins, we explored the use, as vaccine candidates, of virus-like particles (VLPs) containing five different pre-fusion F proteins, including the DS-Cav1 protein. The expression of these five pre-F proteins, their assembly into VLPs, their pre-fusion conformation stability in VLPs, their reactivity with anti-F monoclonal antibodies, and their induction of immune responses after the immunization of mice, were characterized, comparing VLPs containing the DS-Cav1 pre-F protein with VLPs containing four alternative pre-fusion F proteins. The concentrations of anti-F IgG induced by each VLP that blocked the binding of prototype monoclonal antibodies using two different soluble pre-fusion F proteins as targets were measured. Our results indicate that both the conformation and immunogenicity of alternative VLP associated stabilized pre-fusion RSV F proteins are different from those of DS-Cav1 VLPs.

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Formulation of bovine respiratory syncytial virus fusion protein with CpG oligodeoxynucleotide, cationic host defence peptide and polyphosphazene enhances humoral and cellular responses and induces a protective type 1 immune response in mice

Journal of General Virology ◽

10.1099/vir.0.011684-0 ◽

2009 ◽

Vol 90 (8) ◽

pp. 1892-1905 ◽

Cited By ~ 22

Author(s):

J. Kovacs-Nolan ◽

J. W. Mapletoft ◽

Z. Lawman ◽

L. A. Babiuk ◽

S. van Drunen Littel-van den Hurk

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Immune Responses ◽

Fusion Protein ◽

Vaccine Development ◽

Host Defence ◽

Cpg Odn ◽

Cpg Oligodeoxynucleotides ◽

Cpg Oligodeoxynucleotide ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is the leading cause of serious respiratory tract disease in children and calves; however, RSV vaccine development has been slow due to early observations that formalin-inactivated vaccines induced Th2-type immune responses and led to disease enhancement upon subsequent exposure. Hence, there is a need for novel adjuvants that will promote a protective Th1-type or balanced immune response against RSV. CpG oligodeoxynucleotides (ODNs), indolicidin, and polyphosphazene were examined for their ability to enhance antigen-specific immune responses and influence the Th-bias when co-formulated with a recombinant truncated bovine RSV (BRSV) fusion protein (ΔF). Mice immunized with ΔF co-formulated with CpG ODN, indolicidin, and polyphosphazene (ΔF/CpG/indol/PP) developed higher levels of ΔF-specific serum IgG, IgG1 and IgG2a antibodies when compared with ΔF alone, and displayed an increase in the frequency of gamma interferon-secreting cells and decreased interleukin (IL)-5 production by in vitro restimulated splenocytes, characteristic of a Th1 immune response. These results were observed in both C57BL/6 and BALB/c strains of mice. When evaluated in a BRSV challenge model, mice immunized with ΔF/CpG/indol/PP developed significantly higher levels of BRSV-neutralizing serum antibodies than mice immunized with the ΔF protein alone, and displayed significantly less pulmonary IL-4, IL-5, IL-13 and eotaxin and reduced eosinophilia after challenge. These results suggest that co-formulation of ΔF with CpG ODN, host defence peptide and polyphosphazene may result in a safe and effective vaccine for the prevention of BRSV and may have implications for the development of novel human RSV vaccines.

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Chitosan alters inactivated respiratory syncytial virus vaccine elicited immune responses without affecting lung histopathology in mice

Vaccine ◽

10.1016/j.vaccine.2019.06.003 ◽

2019 ◽

Vol 37 (30) ◽

pp. 4031-4039 ◽

Cited By ~ 4

Author(s):

Abenaya Muralidharan ◽

Marsha S. Russell ◽

Louise Larocque ◽

Caroline Gravel ◽

Simon Sauvé ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Virus Vaccine ◽

Lung Histopathology ◽

Syncytial Virus ◽

Respiratory Syncytial Virus Vaccine

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Considerations for a Respiratory Syncytial Virus Vaccine Targeting an Elderly Population

Vaccines ◽

10.3390/vaccines9060624 ◽

2021 ◽

Vol 9 (6) ◽

pp. 624

Author(s):

Laura M. Stephens ◽

Steven M. Varga

Keyword(s):

Respiratory Syncytial Virus ◽

Disease Burden ◽

Elderly Population ◽

Vaccine Development ◽

The Elderly ◽

The United States ◽

Susceptible Population ◽

Age Related ◽

Syncytial Virus ◽

Tract Infections

Respiratory syncytial virus (RSV) is most commonly associated with acute lower respiratory tract infections in infants and children. However, RSV also causes a high disease burden in the elderly that is often under recognized. Adults >65 years of age account for an estimated 80,000 RSV-associated hospitalizations and 14,000 deaths in the United States annually. RSV infection in aged individuals can result in more severe disease symptoms including pneumonia and bronchiolitis. Given the large disease burden caused by RSV in the aged, this population remains an important target for vaccine development. Aging results in lowered immune responsiveness characterized by impairments in both innate and adaptive immunity. This immune senescence poses a challenge when developing a vaccine targeting elderly individuals. An RSV vaccine tailored towards an elderly population will need to maximize the immune response elicited in order to overcome age-related defects in the immune system. In this article, we review the hurdles that must be overcome to successfully develop an RSV vaccine for use in the elderly, and discuss the vaccine candidates currently being tested in this highly susceptible population.

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Effects of dual vaccination for bovine respiratory syncytial virus and Haemophilus somnus on immune responses

Vaccine ◽

10.1016/j.vaccine.2006.03.077 ◽

2006 ◽

Vol 24 (33-34) ◽

pp. 6018-6027 ◽

Cited By ~ 16

Author(s):

L BERGHAUS ◽

L CORBEIL ◽

R BERGHAUS ◽

W KALINA ◽

R KIMBALL ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Bovine Respiratory Syncytial Virus ◽

Haemophilus Somnus ◽

Syncytial Virus

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Construction and characterization of recombinant vaccinia viruses co-expressing a respiratory syncytial virus protein and a cytokine

Journal of General Virology ◽

10.1099/0022-1317-82-9-2107 ◽

2001 ◽

Vol 82 (9) ◽

pp. 2107-2116 ◽

Cited By ~ 20

Author(s):

Teresa R. Johnson ◽

Julie E. Fischer ◽

Barney S. Graham

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Vaccinia Virus ◽

Antigen Expression ◽

Virus Protein ◽

Recombinant Vaccinia ◽

Vaccinia Viruses ◽

Ifn Γ ◽

Syncytial Virus ◽

The Impact

Recombinant vaccinia viruses are well-characterized tools that can be used to define novel approaches to vaccine formulation and delivery. While vector co-expression of immune mediators has enormous potential for optimizing the composition of vaccine-induced immune responses, the impact on antigen expression and vector antigenicity must also be considered. Co-expression of IL-4 increased vaccinia virus vector titres, while IFN-γ co-expression reduced vaccinia virus replication in BALB/c mice and in C57BL/6 mice infected with some recombinant viruses. Protection against respiratory syncytial virus (RSV) challenge was similar in mice immunized with vaccinia virus expressing RSV G glycoprotein and IFN-γ, even though the replication efficiency of the vector was diminished. These data demonstrate the ability of vector-expressed cytokine to influence the virulence of the vector and to direct the development of selected immune responses. This suggests that the co-expression of cytokines and other immunomodulators has the potential to improve the safety of vaccine vectors while improving the immunogenicity of vaccine antigens.

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