Tuesday, July 20, 2010

Inhalable Measles Vaccine Poised to Enter Clinical Trials: The new method could cut vaccine waste

An inhalable, immunogenic vaccine particle has been identified as a lead candidate vaccine for measles and is slated to enter clinical trials in India by summer’s end. Of the 163,000 measles-related deaths of children each year, roughly two-thirds occur in India.

We’re betting that the extraordinary large surface area in the alveoli in the deep lung will give us a therapeutic advantage.
—Robert Sievers, PhD, Colorado University’s Cooperative Institute for Research in Environmental Sciences

Accounting for this high mortality rate, despite the longstanding existence of an effective vaccine, is the phenomenon of “vaccine wastage,” said Robert Sievers, PhD, professor of chemistry and fellow at Colorado University’s Cooperative Institute for Research in Environmental Sciences. Dr. Sievers pioneered the methods used to create the particle.

“Presently, a lyophilized material goes out in multi-dose vials. You reconstitute it with local water that you probably had to purify, then inject one person, then another, but to avoid bacterial contamination you have to destroy what’s left within three to six hours.” The amount of wasted vaccine worldwide is estimated to exceed 40%. Clearly, the conditions on the ground require an innovation in vaccine manufacture.

A Roundabout Path

Despite that need, Dr. Sievers’ goals in embarking on this work were quite different. “For many years, my students and I were concerned about atmospheric quality and pollutants, and especially particulate matter in the air.” The necessity of making reference materials for those studies led to the creation and patenting of a method called carbon dioxide assisted nebulization with a bubble dryer (CAN-BD).

“This gave us nice, fine particles,” said Dr. Sievers. So fine, in fact, that pharmaceutical companies took notice, encouraging Dr. Sievers and his team to increase their study of medical aerosols and eventually leading to the measles project, which was recognized and rewarded with funding by the National Institutes of Health and the Gates Foundation.

“If you think about it,” said Dr. Sievers, “it’s an historical anomaly that we started out sticking needles into your body.” It works, but that doesn’t mean it’s the best way to deliver the active agent. Consider measles, an infection of the lung. “We’re betting that the extraordinary large surface area in the alveoli in the deep lung will give us a therapeutic advantage,” not necessarily superior in immunogenicity to parenteral administration of vaccine, but certainly equivalent.

Particle Size Crucial

The key is particle size, in this case a diminutive dimension that cannot be achieved with commercially available nebulizers like those used for asthma medications. Dr. Sievers discovered that CO2, when it is brought into contact with vaccine under high pressure, creates micro-bubbles that prevent particle aggregation upon drying at atmospheric pressure.

The use of CO2 was combined with an innovation in the constitution of the vaccine. “The biggest challenge in formulation was finding the proper sugar. Sorbitol is the standard, but we used a new inhalable excipient, myo-inositol,” said Dr. Sievers, “that gives you particles that are not nearly as sticky [and are] easily dispersed.” And easy to handle: A vaccine that requires no water or needles can be packaged as a single dose and is inhaled from an easily portable bag, thus minimizing vaccine waste.

“This could well open a new direction for vaccine delivery. I’m eager to see the results of the human trials,” said Tom Jin, MD, of the Aeras Global TB Vaccine Foundation. Dr. Jin’s interest is directly related to the efforts of Aeras, a nonprofit research organization dedicated to the development of new TB vaccines to improve pediatric coverage in developing countries. Aerosol delivery of vaccine is one component of the group’s work.

The foundation’s lead vaccine candidate, AERAS-402, was formulated with mannitol and powdered by way of freeze-drying. Dr. Jin was not eager to reinvent the excipient. “We’re getting two to four micron particle size, and that’s suitable for pulmonary delivery.” The CAN-BD method “is new, and people in the field are very interested in trying it,” he added.

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