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.

Just attended session B6 “Not the Usual Suspects: Community Based Low Tech Interventions that Improve Child Health Outcomes”. Copying the description and presenter info from the conference website here:

Presenters Discuss: the value of pictorial representation of integrated management of childhood illness (IMCI) algorithms and child care best practices for the quality of care of illiterate community health workers (CHWs) (Afghanistan); steps to engage religious leaders in health promotion, capitalizing on traditional vehicles to provide funds to increase health-seeking behaviors, and building an effective rotating drug program (Ethiopia); the role of computer based tools for microplanning in routine immunization and the planning process using the tool (Jharkhand and Madhya Pradesh, India); and how introducing new medicines in Tanzania and the Democratic Republic of Congo (DRC) catalyzed policy changes and drove interventions to strengthen pharmaceutical management systems (Democratic Republic of Congo, Tanzania). 

First a quick recap of the presenters and what they talked about – and then what was most interesting.

One theme that weaved through the first three talks – and one of the most important – was that the success of “low-tech” technology in improving child health depended on an improved understanding of the people that use the technology.

From the first talk (Aitken, Afghanistan): The approach relied on a different type of literacy – a specific symbolic literacy making use of fingers and moons for time, and drawn images of children and mothers. During the formative research, the CHWs asked, in reference to a diagram showing a child being held by her mother, “Where’s the rest of the mother?” The next revision of the C-IMCI materials showed the entire mother, not just a cropping suggesting a mother. There’s a very strong analog to the Pull-Ups diaper case from the consumer packaged goods industry in the United States. First-hand design research with Huggies in the late 1980s showed the difference in perspectives between those producing diapers – exemplified by physical model of a baby without head, arms, or legs – and parents – who were concerned not with sanitation, but childhood development. [on short time now because of the conference - can provide reference later] 

From the second talk (Roy, Ethiopia): Working together with the Ethiopian Orthodox Church, CARE has been engaged in a comprehensive community-based program to improve child health in Ethiopia. The EOC priest delivers health messages after Sunday sermon, on significant holidays, and to 20-40 families that he routinely visits as a “confessor”. Within this framework there are a number of innovations that they have developed tailored to this specific program. The booklet that contains health information is a pamphlet in the same form factor as bibles that the priests carry with them (building trust). Yellow “referral tokens” allow the priest on his household visits to refer a sick child to a local clinic (utilizing non-health professionals for services). They also have a “data board” which publicly displays mortality and morbidity statistics (community information sharing) – it’s a chalkboard much like the community board from Ghana that was making the rounds recently. [can't remember where I saw this, but will add the link if I remember, or if someone reminds me] Finally, the program is extending the traditional economic practice of idir (a traditional membership-based funeral insurance scheme with democratically-elected leadership) to childhood health emergencies.

From the third talk (Sagar, India): The Microsoft Excel-based computer microplanning tool had unexpected positive consequences for those using it at district and sub-district levels. Where no microplanning had been present before, these small health organizations in Jharkand, Uttar Pradesh, and Madhya Pradesh have started to incorporate microplanning into routine activities. Technology for positive organizational change. And the innovation is diffusing organically – the speaker said he received word today that Bihar is starting to use a similar tool in planning routine immunizations.

Here’s an interesting idea from McKinsey – analysing decision maker networks to speed vaccine adoption.

Nearly 11 million children die every year due to a lack of vaccinations. McKinsey research suggests that network analysis, which companies use to improve business outcomes by analyzing information flows and personal relationships, could speed their adoption. Specifically, these techniques can shed light on the complicated processes and interactions that underpin (and often slow down) the introduction of vaccines.

The process of introducing vaccines varies from country to country and involves the influence of many stakeholders—ministries of health and finance, international agencies such as the United Nations Children’s Fund (UNICEF) and the World Health Organization (WHO), nongovernmental organizations (NGOs), community leaders, experts on disease, and funders, to name just some of the players. Defining roles, decision rights, and data requirements for this constellation of participants is difficult. The resulting confusion slows decision making and compounds chronic problems, such as poor infrastructure and limited public-health budgets. Delays, sometimes as long as 15 to 20 years, between the introduction of a vaccine in developed countries and its adoption in developing ones are the result.

Surveys were done on vaccine introductions in Egypt, Mauritania, Mexico, and Zambia. Only Mexico consulted international disease experts, which helped speed adoption of the vaccine. We found as well that in all four countries surveyed, finance representatives either had no role in the process of deciding whether and when to introduce vaccines or were peripheral to it—and usually brought in near its end.

More than 12 years (let that time horizon sink in) after the first indications of success,  there will be a large scale trial for a new malaria vaccine. The potential global health implications of this are obvious, read the full news article, it has some good tidbits in it:

“With the exception of Mosquirix, there’s no possibility of one coming on the market within five or six years…It took eight more years of development and testing before scientists were ready to conduct a large-scale trial of the vaccine. London-based Glaxo and its partners will begin a $100 million study of Mosquirix later this year, vaccinating 16,000 children in seven African countries. If the results are positive, the drug could be on the market as soon as 2011, making it the first vaccine against the deadly disease. “

Full article at Bloomberg (here).  Hat tip to  Families USA.

Friday ended with an impressive lineup of global health leaders discussing the disconnect between horizontal and vertical funding in the plenary session titled Meeting Along the Diagonal: Where the First and Last Mile Connect.  A webcast of this session, and 2-3 others from the Global Health Council Conference, will be available on kaisernetwork.org starting Tues-3-Jun-2008.  It’s nearly 2 hours long, but brings together ideas from the Gates Foundation, WHO, the Global Health Council, and USAID.  As much as it was about these organizations and the types of organizations (foundation, multilateral, advocacy, bilateral), it was about the individuals who spoke their minds:

• Jaime Sepulveda, Director, Integrated Health Solutions Development, Bill & Melinda Gates Foundation
• Margaret Chan, Director-General, World Health Organization
• Nils Daulaire, President and CEO, Global Health Council
• Henrietta H. Fore, Administrator, U.S. Agency for International Development, Director, U.S. United States Foreign Assistance

Friday ended with an impressive lineup of global health leaders discussing the disconnect between horizontal and vertical funding in the plenary session titled Meeting Along the Diagonal: Where the First and Last Mile Connect.  A webcast of this session, and 2-3 others from the Global Health Council Conference, will be available on kaisernetwork.org starting Tues-3-Jun-2008.  It’s nearly 2 hours long, but brings together ideas from the Gates Foundation, WHO, the Global Health Council, and USAID.  As much as it was about these organizations and the types of organizations (foundation, multilateral, advocacy, bilateral), it was about the individuals who spoke their minds:

• Jaime Sepulveda, Director, Integrated Health Solutions Development, Bill & Melinda Gates Foundation
• Margaret Chan, Director-General, World Health Organization
• Nils Daulaire, President and CEO, Global Health Council
• Henrietta H. Fore, Administrator, U.S. Agency for International Development, Director, U.S. United States Foreign Assistance

Friday ended with an impressive lineup of global health leaders discussing the disconnect between horizontal and vertical funding in the plenary session titled Meeting Along the Diagonal: Where the First and Last Mile Connect.  A webcast of this session, and 2-3 others from the Global Health Council Conference, will be available on kaisernetwork.org starting Tues-3-Jun-2008.  It’s nearly 2 hours long, but brings together ideas from the Gates Foundation, WHO, the Global Health Council, and USAID.  As much as it was about these organizations and the types of organizations (foundation, multilateral, advocacy, bilateral), it was about the individuals who spoke their minds:

• Jaime Sepulveda, Director, Integrated Health Solutions Development, Bill & Melinda Gates Foundation
• Margaret Chan, Director-General, World Health Organization
• Nils Daulaire, President and CEO, Global Health Council
• Henrietta H. Fore, Administrator, U.S. Agency for International Development, Director, U.S. United States Foreign Assistance

(Summary of ProMedMail Report of 24 January 2008)

Responding to concerns raised by Indonesia and other developing countries, the WHO has instituted an electronic tracking system to track H5N1 isolates submitted, and what is done with them. Vietnam and Indonesia have provided the most isolates, but are concerned that private companies that are developing vaccines from these isolates will market vaccines that are too expensive for developing countries to purchase in the event of an outbreak. In 2007, as a result of these concerns, Indonesia withheld samples for 5 months.

A country-by-country list of submissions has been created, and the tracking system permits anyone to search for particular isolates by date of submission, source country, host species, and several other variables. The system provides a page of detailed information for each isolate, including a list of all the laboratories to which the virus has been distributed, including pharmaceutical companies.

Read the rest of this entry »

Joint Benefit Concert for the Measles Initiative
BU Law Auditorium
Friday, 13 April 2007, 7:30 pm

Tickets $8 at the door, or email: buredcross@gmail.com.
Sponsored by Harvard, Tufts, BU, & MIT Red Cross Societies
___________

For as little as US $1, one child can be vaccinated against measles. Although measles has been virtually eliminated in the West through effective vaccination, it still kills nearly 454,000 people globally per year. 90% of these deaths are children under five. Measles is one of the leading causes of death among children in most developing countries despite the availability of a safe, effective and relatively inexpensive vaccine for more than 40 years.  Sub-Saharan Africa has the highest burden of measles, and since 2001, efforts by the Measles Initiative have reduced estimated measles cases and deaths by 60%. The effort is now being expanded to Asia.

Children contract measles in overcrowded living conditions (especially refugee camps), at very young ages when their immune systems are not strong, and if they are malnourished. In the West, measles often presents as a mild rash, but in developing conditions, fatal complications can include pneumonia, diarrhea, or brain damage from measles encephalitis.

The Measles Initiative is led by the American Red Cross, with operational support to measles burdened countries. The Initiative follows the WHO/UNICEF strategy, which includes routine vaccination, vaccination campaigns, surveillance of the disease and treatment of sick children with vitamin A in all countries. The inclusion of vaccination campaigns was adopted as a result of the highly successful Rotary effort to eradicate polio, and has a profound impact on reducing measles cases and deaths as it allows health care workers to immunize children who do not have access to routine health services.

Impressively, the campaign has a very clear structure:

1. PLANNING – Coordination among the core partners, in-country partners, and Red Cross national societies to determine target populations, resource needs, and logistics
2. THE COLD CHAIN (supply) – The process of getting the vaccine and all needed supplies from a warehouse in the country to the hundreds of vaccination posts
3. SOCIAL MOBILIZATION (create the demand) – The Red Cross role of spreading the word about the importance of immunization to each family with a child in the targeted age group
4. FOLLOW-UP – Processing the results of the campaign to determine the successes based on coverage, weak points, and future plans

For more information: Measles Initiative

The new combination vaccine candidate Globorix(TM) promises to help control pediatric meningitis in the “meningitis belt” of Africa. Meningitis control has historically depended on expensive last-minute outbreak immunizations, and in 2000, WHO and public health experts called for a sustainable strategy where meningitis vaccine could be administered in general immunization campaigns. Until today no combined conjugate meningococcal vaccine has been available to protect infants in Africa against the disease.

Globorix (TM) is a conjugate vaccine developed by Glaxo-Smith Kline that provides immunity against diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, Neisseria meningitides serogroups A and C. In clinical trials including countries in Africa and Asia, the conjugate meningococcal vaccine has demonstrated a good safety profile and immunogenicity against meningococcal meningitis caused by Neisseria meningitidis serogroups A and C in addition to five other major childhood diseases.

The current meningitis control strategy relies on reactive mass immunization campaigns using polysaccharide vaccines. While these campaigns are estimated to have saved 70% of lives in epidemics, this older type of vaccine has significant drawbacks. Polysaccharide vaccines do not offer protection to infants and in older children and adults they only protect for 3-5 years, leaving them vulnerable to future epidemics. Polysaccharide vaccines also do not address endemic meningitis

Read the full press release here

BBC News Report