Importance and Benefits of Inhaled Vaccines
Humans are naturally exposed to pathogens through the pulmonary, nasal, gastrointestinal, and reproductive mucosa. Therefore, it is crucial to develop strong mucosal immunity at these ports of pathogen entry to provide a first line of defense. A vaccine's delivery route can be integrated with the pathogen's preferred exposure route to generate robust and long-lasting immunity (Figure 1)4. Inhaled vaccines are ideal for respiratory pathogens as they can target the primary site of infection in the lungs5. In addition, inhaled vaccines can provide broader protection in the upper respiratory mucosal sites, such as the throat and nasal passages when administered through the mouth (oral inhalation). A strong mucosal immunity in the upper respiratory tract helps with airway clearance mechanisms, like the cilia and mucous production, to trap and remove inhaled pathogens. Unlike the systemic environment, the respiratory tract has specialized immune cells, including dendritic cells, macrophages, antibodies (IgG and IgA), and lymphocytes (B and T cells). Secretory immunoglobulin A antibodies (SIgA) at mucosal sites can inhibit pathogens from attaching to respiratory epithelial cells and establishing lung infections. The respiratory mucosa is also rich in memory B and T cells, which offer enhanced long-term protection against a pathogen.
Aerosol vaccines offer the benefit of being needle-free alternatives to traditional parenteral vaccines. This can increase vaccine acceptance rates for those who have needlephobia6. Needle-free immunization strategies also simplify the logistics of vaccine administration, making mass immunization campaigns easier to carry out7. Additionally, not relying on needles for vaccine administration can protect healthcare workers from accidental needle-stick injuries, which are often observed in areas with limited resources and inadequately trained healthcare workers8,9. There are unique challenges associated with the development of an aerosol vaccine as will be discussed shortly.
Inhaled Vaccines for Respiratory Infections
Although several clinical studies have investigated the effectiveness of inhaled vaccines, only a few are discussed here. Inhaled measles vaccines have been delivered in liquid and dry powder formulations10,11 and have shown immunogenicity similar to or greater than parenterally delivered vaccine12-14. However, one study found that aerosolized measles vaccines resulted in lower seroconversion rates in children aged nine months compared to those who received the vaccine through subcutaneous administration15. The authors believed that the lower seroconversion was due to the vaccine dose used; however, it might also be attributed to the non-uniform dosing achieved with the air-jet nebulizer employed to administer the vaccine.
The clinical effectiveness of the influenza vaccine has been demonstrated through its targeting of the nasal-associated lymphoid tissue16. Flumist® quadrivalent (Astra Zeneca) is an intranasal (not pulmonary) vaccine recommended for individuals between 2 and 49 years old. It is a live attenuated influenza vaccine (LAIV) containing four strains of weakened virus17. The intranasal administration targets the respiratory mucosa, the primary entry site for the influenza virus.
Clinical trials have also evaluated the effectiveness of aerosolized VLPs against human papillomavirus. As hoped, participants developed SIgA antibodies in their genital tract, which suggested that immune cells had migrated to another mucosal site after receiving the pulmonary vaccine18. Though the aerosol vaccine was well-tolerated, it required a five times higher dose than the IM-delivered dose for seroconversion. The nebulizer used for delivering aerosolized VLPs did not result in significant vaccine deposition in the peripheral lung, potentially compromising the robustness of the immune response. The authors recommended aerosol particle size optimization to increase deep lung deposition for future studies. This issue highlights the challenge with inhaled vaccine delivery, where the outcomes can be influenced by the choice of device and how it is used, a problem rarely observed in parenterally administered vaccines19.
Challenges with the Clinical Development of Inhaled Vaccines
Despite numerous preclinical studies achieving strong immunogenicity and demonstrating efficacy of inhaled vaccines, human trials are rare. As shown in Figure 2, current preclinical techniques for pulmonary delivery do not accurately mimic the breathing maneuvers recommended for humans for proper lung delivery. Inhalation maneuvers in humans include controlling the inhalation flow rate, a breath hold for up to 10 seconds, and varying the inhalation volume and inspiration time, all of which have led to improved lung deposition20,21. Unfortunately, modeling these inhalation maneuvers is difficult in small animal models. The lung anatomy is also different in small animals from humans.
Additionally, the mechanisms for how inhalers work differ between those used in animals and humans19. Dry powder formulations tested in preclinical models are developed with human lung delivery in mind (including the aerodynamic size and particle size distribution). Also, existing inhalers for chronic treatment of asthma and COPD are expensive and unsuitable for large-scale immunization efforts. It is important to develop low-cost and reliable inhalers for vaccine delivery, which can be safely disposed of after a single use.
A Future Perspective on Inhaled Vaccines
To have vaccines accessible for populations in remote regions, it is important to ensure their stability during storage and transportation, which can’t rely on access to refrigeration5. Dry powder formulations with improved room temperature stability have been shown to be effective in achieving this goal22-25. Additionally, compact packaging is necessary for transport of vaccine doses (including any associated device). Therefore, inhalers for vaccine administration should be small, disposable, and affordable. Healthcare professionals must be trained to administer aerosol vaccines to diverse age groups, including pediatric and geriatric populations. Pulmonary immunization offers many advantages over traditional parenteral immunization for those vaccines that may not have the optimal immune response when administered as an injection. However, delivering vaccines via the pulmonary route may require a new development paradigm.
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