Safety and immunogenicity of dry powder measles vaccine administered by inhalation: A randomized controlled Phase I clinical trial

Abstract

a b s t r a c tBackground: Measles is a highly infectious respiratory disease which causes 122,000 deaths annually. Although measles vaccine is extremely safe and effective, vaccine coverage could be improved by a vaccine that is more easily administered and transported. We developed an inhalable dry powder measles vaccine (MVDP) and two delivery devices, and demonstrated safety, immunogenicity, and efficacy of the vaccine in preclinical studies. Here we report the first clinical trial of MVDP delivered by inhalation. Methodology: Sixty adult males aged 18 to 45 years, seropositive for measles antibody, were enrolled in this controlled Phase I clinical study. Subjects were randomly assigned in 1:1:1 ratio to receive either MVDP by Puffhaler ® or by Solovent TM devices or the licensed subcutaneous measles vaccine. Adverse events (AEs) were recorded with diary cards until day 28 post-vaccination and subjects were followed for 180 days post-vaccination to assess potential serious long term adverse events. Measles antibody was measured 7 days before vaccination and at days 21 and 77 after vaccination by ELISA and a plaque reduction neutralization test. Results: All subjects completed the study according to protocol. Most subjects had high levels of baseline measles antibody. No adverse events were reported. MVDP produced serologic responses similar to subcutaneous vaccination. Conclusions: MVDP was well tolerated in all subjects. Most subjects had high baseline measles antibody titer which limited ability to measure the serologic responses, and may have limited the adverse events following vaccination. Additional studies in subjects without pre-existing measles antibody are needed to further elucidate the safety and immunogenicity of MVDP.

Developments in the formulation and delivery of spray dried vaccines

“…2a and 2b ) have been used for delivery of powder measles vaccine in adults males (18 to 45 y age). 91 Delivery by either PuffHaler® or Solovent had a safety (no serious adverse events) and immunogenicity profile (measles IgG antibodies and measles specific neutralizing antibody titers) comparable to that of licensed measles vaccine delivered by the subcutaneous route. Each device disperses powder vaccine into an inexpensive, single-use, disposable reservoir from which the patient inhales, eliminating the risk of cross-contamination.…”

“…The measles spray dried (carbon dioxide assisted nebulization with a bubble dryer) vaccine for pulmonary administration (particle size: 3–5µm), was the first spray dried vaccine to enter phase I clinical trial showing promising results. 91 The study used a spray dried live attenuated measles vaccine with myo-inositol as the stabilizer, substituting sorbitol used in the lyophilized marketed formulation (keeping all other excipients). The vaccine experienced 0.6 log loss in its viral activity during drying and surpassed the WHO stability requirement for freeze-dried measles vaccine (less than 1 log loss in viral activity after 1 week storage at 37°C).…”

“…Various groups are researching the delivery of spray dried vaccines via pulmonary, mucosal, skin and oral routes. 17 , 45 , 48 , 53 , 91 Production of controlled engineered particles of desirable size range gives spray drying the flexibility to produce powder antigens that can be administered via diverse routes of administration. The scope of delivery via different routes is described in the following sections.…”

A stable live bacterial vaccine

“…Our goal for such a vaccine would be to store under refrigeration and transfer to ambient temperature (between RT and 40 ° C) during transportation and immunization; the time when maximum breach in storage conditions usually occur. The spray-drying, modified atmosphere packaging, and storage conditions could be implemented for other live vaccines currently being tested as a pulmonary immunization strategy [14,45].…”

Adjuvantation of Pulmonary-Administered Influenza Vaccine with GPI-0100 Primarily Stimulates Antibody Production and Memory B Cell Proliferation

“…Several small- to large-scale human clinical trials demonstrate that pulmonary immunization in humans is safe and feasible [ 9 , 10 ]. Recently, inhaled live attenuated measles vaccine formulated as aerosol or dry powder was demonstrated to be safe and effective in a Phase I clinical trial [ 11 ].…”