Aerosol vaccination paradigms currently employ delivery of the vaccine directly into the nasal cavity, especially in infants that only breathe through their nasal passages. However, this strategy is not without risk as the proximity of the nasal passages to the olfactory region in the nasal turbinates could result in inadvertent CNS exposure especially if preexisting inflammation is already present in this region. In the case of an LAIV, vaccine could be absorbed from the olfactory mucosa and pass onto the neuronal cells and then onto other parts of the CNS [188]. The possibility for this to occur was studied in adults inhaling aerosols delivered via nasal spray pumps or nebulizers [188]. The study showed the spray pump could not deliver aerosols to the nasal cavity, but a nebulizer was able to do so in part because of the small particle size it could generate, which suggests that small aerosol particles could be deposited in the mucosa of the olfactory region. With the experience gathered from studies done using the inhaled virosomal influenza vaccine, incorporation of adjuvants for inhalation is moving forward with caution. Adjuvants such as Escherichia coli heat-labile toxin (LT) and cholera toxin (CT), while being effective mucosal adjuvants, are believed to target olfactory nerves [189]. Despite the numerous advantages that are associated with aerosol immunization for live-attenuated vaccines, hazards remain regarding potential for transmission of the aerosols generated by the administration device or patient to the vaccine administrators, as well as to the vaccinees’ contacts [126,190]. Several studies with measles, mumps, and rubella vaccines have indicated this potential, and there are documented seropositive responses to measles vaccine (presumably from the aerosol dispenser directly to vaccinators) as well as the previously mentioned LAIV transmission event documented in a daycare setting [126,191].

Host biological processes in response to vaccination may contribute to vaccine- enhanced disease. There are a variety of host responses that help limit infections, mediate vaccine-enhanced disease, or aid in overall disease progression in the patient [192]. For RSV, enhanced respiratory disease (ERD) linked to formalin-inactivated alum-precipitated RSV (FI-RSV) vaccine has forever changed how inactivated RSV vaccines are considered for use in terms of their safety [193]. In the late 1960s, children immunized intramuscularly using the FI-RSV vaccine showed enhanced disease after natural exposure to RSV, with one study noting that 69% of children receiving the immunization had pneumonia compared to just 9% of nonimmunized children in the control group [193,194].

FI-RSV vaccine-enhanced disease was subsequently classified as a severe RSV infection including bronchiolitis and pneumonia, but the majority of the severe and/or fatal vaccinees showed profound mononuclear cell infiltrates as well as pulmonary eosinophilia [193,194]. It is now well substantiated that FI-RSV-enhanced disease includes pulmonary eosinophilia with a substantial inflammatory response [195-197]. The lack of the G protein or G protein CX3C motif during FI-RSV vaccination or RSV challenge of FI-RSV-vaccinated mice or treatment with antisubstance P or anti-CX3CR1 antibodies has been shown to reduce the enhanced pulmonary disease typically observed [195,197]. Therefore, aerosol delivery of FI-RSV or related inactivated RSV vaccines is expected to induce ERD; however, there are no data currently available to confirm this outcome for aerosol-delivered RSV vaccine. It is important to understand the host response to vaccination to avoid unintended biological complications.

Although there are no effective vaccines or drugs for the prevention or treatment of dengue virus, it is an example of a pathogen capable of causing immune-mediated disease [192]. Dengue induces alterations in vascular permeability, hence leading to the translocation of microbial products from the intestinal lumen into the systemic circulation without a concurrent bacteremia [192]. Like RSV, supportive care is the only available treatment. A few live-attenuated vaccine candidates have been tested including intertypic dengue chimeric strains, yellow fever 17D vaccine-dengue chimeras, and flavivirus-nonflavivirus recombinant vaccine vectors [192,198,199]. Passive immunization using antibodies appears to be a viable option relative to the utter lack of effective antiviral treatment options [200]. Presently, there are several vaccine candidates in various stages of testing. The chimeric tetravalent vaccine based on the yellow fever 17D vector may be available in the near future, hence pending the successful outcome of ongoing clinical trials [192,201,202].

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