Intranasal immunization with W₈₀5EC adjuvanted recombinant RSV rF-ptn enhances clearance of respiratory syncytial virus in a mouse model

Abstract

Respiratory Syncytial Virus (RSV) is a ubiquitous virus that infects almost all people by age two and is a major source of respiratory illness in infants, the elderly and others with compromised immune systems. Currently there is no available vaccine. Prior efforts using formalin-inactivated RSV (FI-RSV) were associated with enhanced respiratory disease upon viral exposure following clinical vaccine trials. Several researchers and pharmaceutical companies have utilized vector-associated live attenuated RSV vaccines in pre-clinical and clinical studies. Another attractive approach, however, is a subunit vaccine which would be easier to produce and quality control. Our group has previously demonstrated in a murine model of infection that intranasal immunization with nanoemulsion-inactivated and adjuvanted RSV induces humoral and cellular immune responses, resulting in protection against RSV infection. The present studies characterize the immune responses elicited by intranasal RSV F protein adjuvanted with nanoemulsion. Intranasal application of nanoemulsion adjuvanted F protein induced a rapid and robust systemic and mucosal antibody response, as well as protection against subsequent RSV challenge. Importantly, RSV challenge in immunized animals did not elicit airway hyper-reactivity, a Th2-skewed immune response or immunopathology associated with hypersensitivity reactions with formalin-inactivated vaccine. These results suggest that RSV F protein adjuvanted with nanoemulsion may be a good mucosal vaccine candidate. Formulating RSV F protein in nanoemulsion creates a well-defined and well-controlled vaccine that can be delivered intranasally to induce T cell mediated immunity without inducing enhanced disease associated with the mouse model of FI-RSV vaccination and infection.

The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics

“…A variety of animal models exist to research respiratory viruses such as influenza [124][125][126], RSV [127][128][129][130][131][132][133][134][135][136][137], HRV [22,[138][139][140]. No single animal offers a platform for all respiratory viruses that infect humans, and different animal models exist for the same virus, which can give different, often conflicting results.…”

Intranasal nanoemulsion-based inactivated respiratory syncytial virus vaccines protect against viral challenge in cotton rats

“…[14][15][16] In mice, intranasal immunization with RSV-nanoemulsion adjuvanted-based vaccines in mice does not result in a hyper-Th2 response either prior to or post-infection. 28,29 This study in the cotton rat model again demonstrates that these nanoemulsion adjuvants induce Th1 skewed cellular immunity to RSV. The high amounts of IFN-g secreted by splenocytes suggest that IFN-g secreting effector cells may play an important role in protection.…”

“…Overall, these results support our previous data in mice that nanoemulsion-based RSV vaccines elicit the production of Th1 (IFN-g) cytokines. 28,29 Histopathology In order to assess the impact of RSV L19 vaccination on histological changes after subsequent infection with RSV A2, we performed H&E staining of tissue sections from the lungs of cotton rats 4 and 8 d post-challenge. Prior to challenge, there were no detectable differences in the lungs of cotton rats that had been immunized compared to na€ ıve animals, demonstrating that immunization alone does not induce any histopathological changes in the lungs (data not shown).…”

“…26 NE adjuvants have been shown to generate robust, protective immune responses in mice and other rodents for a variety of different pathogens, including anthrax, influenza, hepatitis B, vaccinia and RSV. [23][24][25][26][27][28][29][30][31][32][33][34][35] Live RSV is inactivated directly by the NE. The resulting inactivated virus retains the native antigen structure, unlike chemical inactivation which can alter the structure of epitopes critical for mounting an immune response appropriate for the virus.…”

“…34 Previous studies have demonstrated that intranasal immunization of mice with a W 80 5EC NE-based whole RSV or RSV fusion glycoprotein (F protein) vaccine led to humoral and cellular immune responses, including mucosal antibody production. 28,29 These vaccinations conferred protection against RSV L19 challenge without the induction of Th2 cytokines or pathological changes associated with the mouse model of RSV infection. Although encouraging, these murine studies cannot solely be used to determine the effectiveness of RSV vaccines because mice are not particularly susceptible to RSV infection.…”