Successful respiratory immunization with dry powder live-attenuated measles virus vaccine in rhesus macaques

Abstract

Measles remains an important cause of childhood mortality worldwide. Sustained high vaccination coverage is the key to preventing measles deaths. Because measles vaccine is delivered by injection, hurdles to high coverage include the need for trained medical personnel and a cold chain, waste of vaccine in multidose vials and risks associated with needle use and disposal. Respiratory vaccine delivery could lower these barriers and facilitate sustained high coverage. We developed a novel single unit dose, dry powder live-attenuated measles vaccine (MVDP) for respiratory delivery without reconstitution. We tested the immunogenicity and protective efficacy in rhesus macaques of one dose of MVDP delivered either with a mask or directly intranasal with two dry powder inhalers, PuffHaler and BD Solovent. MVDP induced robust measles virus (MeV)-specific humoral and T-cell responses, without adverse effects, which completely protected the macaques from infection with wild-type MeV more than one year later. Respiratory delivery of MVDP was safe and effective and could aid in measles control.aerosol delivery | protective immunity | multifunctional T cells | antibody avidity M easles is a highly contagious viral disease. Before the availability of measles virus (MeV) vaccines, more than 130 million cases and 7-8 million deaths occurred annually. Intensive immunization efforts with the live attenuated measles vaccine (LAMV) given by injection have resulted in substantial decreases in global measles disease. However, with an estimated 164,000 deaths in 2008 (1), measles continues to be an important cause of child mortality, especially in less-developed regions of the world. The key to prevention of measles is achieving and sustaining high levels of population immunity through vaccination, and substantial challenges for high coverage remain in many countries. Some of the challenges to providing a first dose of measles vaccine to at least 95% of each birth cohort, plus a second dose to older children, are related to the method of vaccine delivery.Measles vaccine is given by injection, and this creates hurdles to sustained high coverage in many developing countries. First, there is often a shortage of the trained personnel needed for sterile reconstitution and safe injection of vaccine. Second, in most developing countries, lyophilized vaccine is in 5-10 dose vials that, after reconstitution, lose 30-50% potency in an hour at 37°C (2), so unused doses must be discarded. Third, contaminated needles and syringes create risks for transmitting bloodborne disease and require safe disposal.As a potential improvement, respiratory delivery of reconstituted liquid LAMV has been studied for more than three decades (3) but has never been licensed or widely used. Aerosol administration of aqueous vaccine is highly effective in boosting preexisting antibody and holds promise for use in older children (4-11), but primary humoral and cellular immune responses vary with the age of vaccinees (12-15).We have developed a dry powder formulation of ...

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

“…However, delivery of the powder measles vaccine was not successful in producing immune responses in preclinical trials in non-human primates [35]. In contrast, MVDP was immunogenic in rhesus macaques and protected these animals from challenge with measles virus [24].…”

“…MVDP developed satisfactory immune responses in cotton rats [23]. When delivered by mask or nasal prong, MVDP was shown to produce robust immune responses in non-human primates, similar to vaccination by injection and to protect from challenge with wild-type measles virus [24]. MVDP was also found safe in licensure level animal toxicity studies (unpublished data).…”

Deposition of Dry Powder Generated by Solovent in Sophia Anatomical Infant Nose-Throat (SAINT) Model

“…Secondly, it was recently used to administer powder measles vaccine to rhesus macaques, which are obligate nose-breathers like human infants. In those studies, dosing with the Solovent was sufficient to completely protect against a subsequent measles virus exposure (Lin et al 2011).…”

Inhalable Antibiotics Manufactured Through Use of Near-Critical or Supercritical Fluids

“…The new PuffHaler, described in Figure 2, is an active DPI, with a disposable mask suitable for use with infants or test animal subjects such as cotton rats (Kisich et al 2011), and rhesus macaques (Lin et al 2011).…”