While nasal sprays reach primarily the nose and throat, inhaled aerosols bypass the nasal passage and deliver vaccine droplets deep in the airway, where they can induce a broad protective immune response, the researchers report.
For the study, published online in the journal Frontiers in Immunology, the researchers used a tuberculosis vaccine to compare delivery methods by measuring the distribution of droplets, immune responses and potency in animals.
“Infections in the upper respiratory tract tend to be non-severe. In the context of infections caused by viruses like influenza or SARS-CoV-2, it tends to be when the virus gets deep into the lung that it makes you really sick,” explains Matthew Miller, a co-author of the study who holds the Canada Research Chair in Viral Pandemics at McMaster University.
“The immune response you generate when you deliver the vaccine deep into the lung is much stronger than when you only deposit that material in the nose and throat because of the anatomy and nature of the tissue, and the immune cells that are available to respond are very different,” says Miller, who is also an investigator with Canada’s Global Nexus for Pandemics & Biological Threats, which is based at McMaster.
“This study for the first time provides strong preclinical evidence to support the development of inhaled aerosol delivery over nasal spray for human vaccination against respiratory infections including TB, COVID-19 and influenza,” says Zhou Xing, co-investigator of the study and a professor at the McMaster Immunology Research Centre and Department of Medicine.
More than 6.3 million have people died during the COVID-19 pandemic, and respiratory infections remain a significant cause of illness and death throughout the world, driving an urgent and renewed worldwide effort to develop vaccines that can be delivered directly to the mucous lining of the respiratory tract.
A Phase 1 clinical trial is currently under way to evaluate the inhaled aerosol vaccine in healthy adults who had previously received two or three doses of an injected COVID mRNA vaccine.
Previous research by the McMaster team has shown that in addition to being needle-free and painless, an inhaled vaccine is so efficient at targeting the lungs and upper airways that it can achieve maximum protection with a much smaller dose than injected vaccines.
Pulmonary tuberculosis (TB) continues to be a major global health issue, accounting for 1.4 million deaths and 10 million new cases in 2019 (1). BCG, as the most administered human vaccine — which is given via the skin shortly after birth — has failed to effectively control TB in adults. In the last couple of decades, great strides have been made in developing new TB vaccine candidates (2).
However, the vast majority of these vaccines were designed for the parenteral route of administration, which is known to induce poor respiratory mucosal immunity (3). Thus, a safe and effective boost vaccine strategy is urgently needed for much-improved protective immunity in the lung (2, 3).
Among the promising vaccine platforms is a recombinant replication-defective human serotype 5 adenovirus-vectored (AdHu5-vectored) TB vaccine expressing M. tuberculosis antigen 85A (AdHu5Ag85A). This vaccine has been extensively evaluated in a number of preclinical models, shown to be highly effective when administered via the respiratory tract, as opposed to its parenteral delivery (3, 4). Besides its superior effects in inducing lung tissue resident memory T cells (TRM) (3), AdHu5Ag85A delivered via the respiratory mucosa is able to elicit long-lasting memory airway macrophages and trained innate immunity (5, 6).
It is widely believed that the most effective vaccine strategy ought to induce both innate memory and adaptive memory responses (5, 7). However, it remains unclear whether such highly compartmentalized distribution of immunity dictated by the route of Ad-vectored immunization is also true in humans. Although AdHu5Ag85A was evaluated successfully in healthy humans following i.m. injection (8, 9), its suitability for respiratory mucosal delivery and its safety and immunogenicity remain to be determined in healthy humans.
Recent studies have shown inhaled aerosol to be a safe and effective delivery method for a respiratory mucosal route of immunization in healthy humans with measles and MVA85A vaccines (10–13). However, these studies applied different technologies for aerosol delivery. Since aerosol characteristics and delivery efficiency may vary according to the type of vaccine, an aerosol delivery technology remains to be characterized and validated for administering Ad-vectored vaccine to the human airway.
Given that a number of currently approved COVID-19 vaccines are also based on adenoviral vector, it is highly relevant to fully characterize an inhaled aerosol delivery technology for Ad-vectored vaccine and investigate its ability to induce respiratory mucosal immunity in preparation for its translation to respiratory mucosal COVID-19 vaccine strategies (14). Such next-generation COVID-19 vaccine strategies are urgently needed in the face of increasing breakthrough infections due to the variants of concern and waning vaccine-induced immunity (15).
In the present study, we have characterized the property of AdHu5Ag85A aerosol droplets generated by the Aeroneb Solo nebulizer. We evaluated the 2 aerosol doses and compared the safety and immunogenicity of the vaccine delivered via the respiratory mucosal route or i.m. route in previously BCG-vaccinated healthy adults. Our study is the first to our knowledge to safely deliver an Ad-vectored vaccine via inhaled aerosol to humans and to demonstrate its superiority in inducing respiratory mucosal immunity over i.m. injection.
reference link : https://insight.jci.org/articles/view/155655
Journal information: Frontiers in Immunology
