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

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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Efficacy of high dose-short duration ribavirin aerosol in the treatment of respiratory syncytial virus infected cotton rats and influenza B virus infected mice

Antiviral Research ◽

10.1016/0166-3542(87)90029-5 ◽

1987 ◽

Vol 7 (4) ◽

pp. 211-220 ◽

Cited By ~ 42

Author(s):

P WYDE ◽

S WILSON ◽

R PETRELLA ◽

B GILBERT

Keyword(s):

Respiratory Syncytial Virus ◽

Short Duration ◽

Influenza B Virus ◽

Influenza B ◽

High Dose ◽

B Virus ◽

Cotton Rats ◽

Syncytial Virus

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Parainfluenza Virus 5 Expressing Wild-Type or Prefusion Respiratory Syncytial Virus (RSV) Fusion Protein Protects Mice and Cotton Rats from RSV Challenge

Journal of Virology ◽

10.1128/jvi.00560-17 ◽

2017 ◽

Vol 91 (19) ◽

Cited By ~ 10

Author(s):

Shannon I. Phan ◽

James R. Zengel ◽

Huiling Wei ◽

Zhuo Li ◽

Dai Wang ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Fusion Protein ◽

Vaccine Candidate ◽

Parainfluenza Virus ◽

Wild Type ◽

Rsv Infection ◽

Cotton Rats ◽

Parainfluenza Virus 5 ◽

Syncytial Virus ◽

Vectored Vaccine

ABSTRACT Human respiratory syncytial virus (RSV) is the leading cause of pediatric bronchiolitis and hospitalizations. RSV can also cause severe complications in elderly and immunocompromised individuals. There is no licensed vaccine. We previously generated a parainfluenza virus 5 (PIV5)-vectored vaccine candidate expressing the RSV fusion protein (F) that was immunogenic and protective in mice. In this work, our goal was to improve the original vaccine candidate by modifying the PIV5 vector or by modifying the RSV F antigen. We previously demonstrated that insertion of a foreign gene at the PIV5 small hydrophobic (SH)–hemagglutinin-neuraminidase (HN) junction or deletion of PIV5 SH increased vaccine efficacy. Additionally, other groups have demonstrated that antibodies against the prefusion conformation of RSV F have more potent neutralizing activity than antibodies against the postfusion conformation. Therefore, to improve on our previously developed vaccine candidate, we inserted RSV F at the PIV5 SH-HN gene junction or used RSV F to replace PIV5 SH. We also engineered PIV5 to express a prefusion-stabilized F mutant. The candidates were tested in BALB/c mice via the intranasal route and induced both humoral and cell-mediated immunity. They also protected against RSV infection in the mouse lung. When they were administered intranasally or subcutaneously in cotton rats, the candidates were highly immunogenic and reduced RSV loads in both the upper and lower respiratory tracts. PIV5-RSV F was equally protective when administered intranasally or subcutaneously. In all cases, the prefusion F mutant did not induce higher neutralizing antibody titers than wild-type F. These results show that antibodies against both pre- and postfusion F are important for neutralizing RSV and should be considered when designing a vectored RSV vaccine. The findings also that indicate PIV5-RSV F may be administered subcutaneously, which is the preferred route for vaccinating infants, who may develop nasal congestion as a result of intranasal vaccination. IMPORTANCE Despite decades of research, human respiratory syncytial virus (RSV) is still a major health concern for which there is no vaccine. A parainfluenza virus 5-vectored vaccine expressing the native RSV fusion protein (F) has previously been shown to confer robust immunity against RSV infection in mice, cotton rats, and nonhuman primates. To improve our previous vaccine candidate, we developed four new candidates that incorporate modifications to the PIV5 backbone, replace native RSV F with a prefusion-stabilized RSV F mutant, or combine both RSV F and PIV5 backbone modifications. In this work, we characterized the new vaccine candidates and tested their efficacies in both murine and cotton rat models of RSV infection. Most importantly, we found that PIV5-based RSV vaccine candidates were efficacious in preventing lower respiratory tract infection as well as in reducing the nasal viral load when administered via the subcutaneous route.

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Priorities for developing respiratory syncytial virus vaccines in different target populations

Science Translational Medicine ◽

10.1126/scitranslmed.aax2466 ◽

2020 ◽

Vol 12 (535) ◽

pp. eaax2466 ◽

Cited By ~ 5

Author(s):

Simon B. Drysdale ◽

Rachael S. Barr ◽

Christine S. Rollier ◽

Christopher A. Green ◽

Andrew J. Pollard ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Vaccine Development ◽

Current Knowledge ◽

Clinical Development ◽

Effective Vaccine ◽

Susceptibility To Infection ◽

Target Populations ◽

Syncytial Virus ◽

The 1960S

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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Resistance to human respiratory syncytial virus (RSV) infection induced by immunization of cotton rats with a recombinant vaccinia virus expressing the RSV G glycoprotein.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.83.6.1906 ◽

1986 ◽

Vol 83 (6) ◽

pp. 1906-1910 ◽

Cited By ~ 45

Author(s):

N. Elango ◽

G. A. Prince ◽

B. R. Murphy ◽

S. Venkatesan ◽

R. M. Chanock ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Vaccinia Virus ◽

Recombinant Vaccinia Virus ◽

Human Respiratory Syncytial Virus ◽

Recombinant Vaccinia ◽

Rsv Infection ◽

Cotton Rats ◽

Syncytial Virus

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Minimum high dose ribavirin aerosol for the treatment of influenza in mice and respiratory syncytial virus in cotton rats

Antiviral Research ◽

10.1016/0166-3542(91)90273-t ◽

1991 ◽

Vol 15 ◽

pp. 142

Author(s):

B.E. Gilbert ◽

P.R. Wyde ◽

M.W. Ambrose ◽

H.L. Mover ◽

S.Z. Wilson

Keyword(s):

Respiratory Syncytial Virus ◽

High Dose ◽

Cotton Rats ◽

Syncytial Virus

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Enhancement of Respiratory Syncytial Virus Pulmonary Pathology in Cotton Rats by Prior Intramuscular Inoculation of Formalin-Inactivated Virus

Journal of Virology ◽

10.1128/jvi.59.1.193-193.1986 ◽

1986 ◽

Vol 59 (1) ◽

pp. 193-193

Keyword(s):

Respiratory Syncytial Virus ◽

Intramuscular Inoculation ◽

Cotton Rats ◽

Pulmonary Pathology ◽

Syncytial Virus

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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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Shifting immunodominance pattern of two cytotoxic T-lymphocyte epitopes in the F glycoprotein of the Long strain of respiratory syncytial virus

Journal of General Virology ◽

10.1099/vir.0.80219-0 ◽

2004 ◽

Vol 85 (11) ◽

pp. 3229-3238 ◽

Cited By ~ 28

Author(s):

Carolina Johnstone ◽

Patricia de León ◽

Francisco Medina ◽

José A. Melero ◽

Blanca García-Barreno ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Vaccinia Virus ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Recombinant Vaccinia Virus ◽

Recombinant Vaccinia ◽

F Protein ◽

Syncytial Virus ◽

Lymphocyte Responses

Human respiratory syncytial virus (RSV) is a major cause of respiratory infection in children and in the elderly. The RSV fusion (F) glycoprotein has long been recognized as a vaccine candidate as it elicits cytotoxic T-lymphocyte (CTL) and antibody responses. Two murine H-2Kd-restricted CTL epitopes (F85–93 and F92–106) are known in the F protein of the A2 strain of RSV. F-specific CTL lines using BCH4 fibroblasts that are persistently infected with the Long strain of human RSV as stimulators were generated, and it was found that in this strain only the F85–93 epitope is conserved. Motif based epitope prediction programs and an F2 chain deleted F protein encoded in a recombinant vaccinia virus enabled identification of a new epitope in the Long strain, F249–258, which is presented by Kd as a 9-mer (TYMLTNSEL) or a 10-mer (TYMLTNSELL) peptide. The results suggest that the 10-mer might be a naturally processed endogenous Kd ligand. The CD8+ T-lymphocyte responses to epitopes F85–93 and F249–258 present in the F protein of RSV Long were found to be strongly skewed to F85–93 in in vitro multispecific CTL lines and in vivo during a secondary response to a recombinant vaccinia virus that expresses the entire F protein. However, no hierarchy in CD8+ T-lymphocyte responses to F85–93 and F249–258 epitopes was observed in vivo during a primary response.

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