Credit: PATH

As reported recently on Xconomy.com, scientists at PATH—a Seattle-based nonprofit organization working to improve global health and well-being—have found a cheap and simple way to tackle the challenges associated with protecting hepatitis B vaccine effectiveness when the vaccine gets too hot or too cold. Given how important this development seems, I contacted PATH to ask them some additional questions about this important breakthrough which they have kindly taken a lot of time to answer (many thanks to Amy for working with me on this). The e-interview consisted of the following 8 questions:

1. What was the primary breakthrough?

2. How did you get this done?

3. Why was no one else able to do this before?

4. What are the barriers to applying this to other vaccines? AND how does this change the costs of delivering vaccines in general (does the cost structure change in any way)?

5. What was the approximate cost to achieve this?

6. On the surface this appears to be a major breakthrough, is that how PATH scientists are viewing this?

7. Have you done projections on the increased number of vaccinations that can be done with this new technology?

8. Is this something that can be used in OECD markets?

Temperature regulation is one of the biggest challenges to vaccine use worldwide. According to PATH, keeping some vaccines at stable temperatures requires the use of a vaccine cold chain — a global distribution network of refrigeration equipment and procedures for maintaining vaccine quality during transport and storage. Cold chain storage and exposure to extreme temperatures presents a critical obstacle to delivering needed vaccines to some of the most at-risk regions around the globe. Other research teams in addition to PATH’s are currently using various innovations to address the problem. A group of researchers at the University of Colorado at Boulder, for example, is developing a powdered, inhalable version of a measles vaccination that is ready for human testing. With regards to PATH’s work, the full e-interview is below:

E-INTERVIEW WITH PATH

What was the primary breakthrough?
One of the biggest challenges to vaccine use is temperature regulation. World Health Organization guidelines recommend that nearly all vaccines be stored at 2°C to 8°C. These temperature requirements necessitate use of a vaccine cold chain—a global distribution network of refrigeration equipment and procedures for maintaining vaccine quality during transport and storage.

In many parts of the world, the need to keep vaccines cold during transport and storage requires allocation of scarce resources to cover costs for refrigeration equipment and special handling procedures. A growing body of research indicates that cold chain storage facilities are insufficient to handle the increasing number of vaccines that are being introduced in immunization programs. In addition, vaccines are frequently damaged when they are accidentally or inadvertently frozen or exposed to heat—which, in turn, greatly affects vaccine effectiveness. Improving both the heat- and freeze-stability of a vaccine can help with these issues. Heat- and freeze-stable vaccines are more resistant to damage when temperatures rise and fall due to power outages, faulty refrigeration equipment, or handling errors. Heat-stable vaccines could potentially be moved to storage at higher temperatures (with appropriate controls) to provide space for less heat-stable vaccines.

The heat-stable hepatitis B vaccine recently developed by PATH and partners could be kept in alternate storage facilities (such as air-conditioned rooms) and under alternative transport conditions (such as insulated packaging without ice packs) for potentially its entire shelf life without compromising the effectiveness of the vaccine. The added heat stability can also facilitate outreach to remote areas and enable better heath outcomes when health care providers, for example, travel to remote areas to deliver the necessary birth dose of hepatitis B vaccine to hard-to-reach populations.

Altogether, the heat- and freeze-stabilization of common vaccines, like hepatitis B vaccine, has the potential to improve immunization effectiveness and efficiency—to help to extend immunization coverage by simplifying the logistics and reducing the costs associated with transport and storage of vaccines in regions of the world where the cold chain is insufficient, impractical, or otherwise constrained.

How did you get this done?
PATH and partners tested many formulation approaches and perfected a particularly promising one that combines a freeze-protection method developed last year by PATH with a heat stabilization method previously developed by Arecor. The approach, once tested and refined, includes the addition of common stabilizers to hepatitis B vaccine formulations.  The stabilizers used include propylene glycol—a compound that is found in many consumer products, foods and medicines, and protects the vaccine from cold—and an amino acid called histidine, which contributes to the vaccine’s heat-stabilization.

According to research findings recently published in a July issue of Vaccine (volume 27, issue 34), this freeze- and heat-stable formulation was found to be well tolerated in animal models without any significant local or systemic side effects.  Tests of the new formulation also showed it to be heat-stable for 12 months at 37°C in addition to proving freeze-stable at ?20°C. In partnership with Arecor and the University of Colorado Denver School of Pharmacy, PATH published more recent findings in the August issue of Human Vaccines (volume 5, issue that describe the new hepatitis B vaccine formulation exhibiting nine week heat stability at 55°C and at least six month stability at both 37°C and 45°C.

Why was no one else able to do this before?
To our knowledge, researchers have not previously sought solutions to protect vaccine from freeze-damage through formulation methods. Vaccines that are freeze-sensitive are simply labeled as such and the burden is on health care providers to keep the vaccine at appropriate temperatures. A concerted effort by PATH scientists over a number of years—with support for our project work in vaccine stabilization, funded by the Bill & Melinda Gates Foundation—allowed PATH to tackle this issue head on. The freeze-stabilization method should apply equally-well to all vaccines containing aluminum adjuvant. The heat protection method also arose out of PATH’s vaccine stabilization project and applies a technology from commercial partner, Arecor, to hepatitis B vaccine, which is an important childhood vaccine that is often distributed and used in difficult settings—thus requiring outreach to hard-to-reach areas (to deliver it to newborns in their home).

What are the barriers to applying this to other vaccines? AND how does this change the costs of delivering vaccines in general (does the cost structure change in any way)?
The costs of both additives, propylene glycol and histidine, are neglible.  Scientists at PATH say that the additives cost an extra one-tenth of one US penny per vaccine dose. However, the hepatitis B vaccine is a mature product that has been on the market for some time. To stabilize this vaccine now requires reformulation—plus all the necessary laboratory, preclinical, and clinical work to validate that the new product is still as effective as the existing product. The product must also receive regulatory approval.

Presently, the heat and freeze-stabilization technology has been transferred to one vaccine producer that is undertaking this work to achieve a superior hepatitis B vaccine. By comparison, the freeze-stabilization technology is broadly applicable to all vaccines containing aluminum adjuvant and could be added to any new vaccine incorporating this type of adjuvant. PATH has placed the freeze-stabilization technology in the public domain to encourage uptake.

What was the approximate cost to achieve this?
The development of these formulation methods and the research described in both published studies were conducted in conjunction with PATH’s broad project work in vaccine stabilization funded by the Bill & Melinda Gates Foundation.

On the surface this appears to be a major breakthrough, is that how PATH scientists are viewing this?
Yes, it represents a major breakthrough because the research shows how we can now prevent the problem from the beginning through the vaccine formulation itself.  The application of heat and freeze stabilization technologies to new vaccine products represents a sea change, of sorts, in how vaccine producers could optimize vaccine products—and, in turn, ease logistics for immunization programs as well as expand the reach and ensure the effectiveness of life-saving vaccines.

Have you done projections on the increased number of vaccinations that can be done with this new technology?
It is difficult to project because of the many additional factors that effect increases in the number of vaccinations, for example, the availability of health care workers and transportation for outreach.  That said, PATH has analyzed the projected health impacts and the cost-effectiveness of introduction of thermostable vaccines into three countries—Bangladesh, Cambodia, and Ghana.  For more information, please contact us by email (info@path.org).

Is this something that can be used in OECD markets?
Yes, the heat and freeze stabilization technologies have the potential to optimize vaccine products for OECD markets, as well as vaccine products used by immunization programs in emerging and resource-poor settings.  The challenges associated with maintaining vaccine temperature requirements during storage and transport are not limited to the developing world.  No matter the country, vaccine damage caused by heat or freezing is not a simple problem—it is hard to detect.  You can’t always tell whether or not a vaccine has been rendered ineffective simply by looking at it.  The U.S. Centers for Disease Control and Prevention estimates that poor refrigeration wastes hundreds of thousands of doses of vaccine every year, costing the U.S. health care system millions of dollars and, when noticed, requiring children and others who need vaccination to be reimmunized.