Emerging Infections of International Public Health Importance

Objectives:

To give a brief history of global immunization
To understand the issues of introducing new vaccines
Understand problems in global immunization
Understand GAVI and the Vaccine Fund

I would like to give a brief overview of current global immunization issues including a brief, biased history of global immunization issues, introduce some of the newer vaccines using the example of hepatitis B vaccine, discuss current problems in global immunization, and discuss some possible solutions.

We believe that every child has the right to benefit from traditional and newer life saving vaccines delivered safely regardless of socioeconomic level or country of residence. Not everybody agrees, but many of us who are in the vaccine business are very motivated by this.

The other belief is that the global community is obligated to ensure that this "right" and benefit is achieved if national governments cannot or will not do it. I believe that a "right" is meaningless unless it places a duty on other to see it happen.

The EPI is a network of the national immunization programs of every country and the efforts of many partners. Before the EPI system, vaccines predominately benefited children in industrialized countries. Beginning in the 1970’s with the smallpox eradication program, it was shown that immunizations could reach even the most remote areas of the world. This event changed immunization strategies tremendously. In 1970’s only 5% of the worlds children were vaccinated. By 1990 vaccines reach over 75% of the world’s children. This is probably the greatest public health achievement in history.

This shows the history of the development of the EPI between the mid ‘70’s where there was about 5% coverage up to the 1990’s

This slide shows that immunization coverage is not equal in all parts of the world. Some areas such as sub-Saharan Africa only reach 50% immunization coverage.

Immunization is one of medicine’s greatest and most cost effective gifts to mankind. But the greatest potential of immunization is not yet realized. The vaccines against the 8 EPI diseases could prevent about 7 million deaths per year. New vaccines have the potential to prevent an additional 15 million deaths.

This slide shows the potential for life saved by use of the vaccine preventable disease. In the middle are the EPI plus target diseases. The last diseases are common infections world wide for which no vaccine exist at present

The classic vaccine was produced by inactivating or attenuating the pathogen. This is a slow process. The newer technologies have allowed multiple ways to make vaccines through the use of molecular cloning.

This newer technology is allowing us to make vaccines against pathogens the old method would not allow. The insertion of a surface protein from hepatitis B virus into yeast and then purified is one of the first examples of the new technology’s success.

During the 1970’s and 1980’s the immunization community was primarily interested in building infrastructure of training people, getting refrigerators and cold change distributors, using the traditional 6 EPI vaccines (DTP, Polio, Measles and BCG). These vaccines are very inexpensive to produce, costing pennies per dose. There is little interest in newer antigen vaccines such as Hepatitis B for many reasons including not being seen as an important disease, higher cost, and not a "child survival" issue. Other issues include a protection of the intellectual property, use of higher and more expensive technology, need for pharmaceutical research and development to get to licensure of new vaccines, and the lack of a financial infrastructure to support global immunization of newer vaccines.

We need to try and influence the availability of these newer vaccines into developing countries. The hepatitis B vaccine was available in the United States in 1982, it wasn’t until 2001 that this vaccine was available as part of the global immunization strategy.

We need to shorten the gap to introduction of new vaccines, encourage the development of new antigens that are of less commercial interest, and insure that studies address global issues early in the research and development stage.

The traditional 6 vaccines of the EPI cost a total of $0.70 per child. UNICEF spends less than 100 million dollars for 1 billion doses of vaccine. Even at $0.70 per dose, a new vaccine could triple the current cost. Pneumococcal vaccines could cost 10 times this amount. New vaccines have to compete with other scarce human and financial resources at all levels in many of these countries.

There are about 350 million chronic carriers of hepatitis B worldwide. Twenty five percent of those infected will die from chronic liver disease such as cirrhosis or liver cancer. The hepatitis B vaccine could prevent more than 1 million deaths per year if every child in the world received the vaccine. The main reason is that 85-90% of cirrhosis and liver cancer from hepatitis B is vaccine preventable.

The map shows the seroprevalence of hepatitis B worldwide. As you can see the disease is not evenly distributed with the poorest parts of the world with the highest burden. More than 8% of the population in sub-Saharan Africa and Asia are chronically infected compared to less than 2% in North America and Europe.

This graph compares the total cancer rates in Gambia, West Africa to those of liver cancer. Almost all of the liver cancer rates are due to hepatitis B chronic infection

The hepatitis B DNA recombinant vaccine is now manufactured in several countries including Japan, Korea, India, Brazil and Cuba. The price of the vaccine has decreased from $30 per dose to less than $0.30 per dose for the public sector. It is also available in combination with other EPI vaccines such as DTP-HB and DTP-HB-HIB.

In 1991 the World Health Assembly made to recommendation that hepatitis B vaccine should be integrated into national immunization programs in all countries with a hepatitis B carrier prevalence (HBsAg) of 8% or greater by 1995 and in all countries by 1997. Unfortunately, this did not happen.

This slide shows what the hepatitis B vaccine can do in a high prevalence country. This data from Shanghai’s, China compares data of hepatitis B carrier status before immunization (1988-1994) with 14% of the population under the age of 7 being infected to after vaccination where the rates are less than 1% across the age distribution.

This slide looks at the HBsAg carrier prevalence in several countries before and after vaccination with hepatitis B. As you can see in all circumstances the rate of chronic hepatitis B infection was able to be decreased to less than 2%.

By 1999 approximately 110 countries had introduced the hepatitis B vaccine and had a national program as shown in the darker color here. Other countries were in the planning stages. However, sub-Saharan Africa continues to show a lack of any program or even planning where the need seems to be most urgent.

This slide compares the log GNP to the log population of the countries listed. This shows that if a country has a GNP of less than $500 US, the vaccine was generally unavailable. This corresponded to many countries that had high endemnicity of the virus. If they had more than $550 US GNP the countries were able to afford the vaccine. This showed that vaccination was following the economics rather than the epidemiologic realities.

One of the explanations for this discrepancy may be explained by the decline in the immunization programs from 1980 to 1990. In 1980, the Universal Childhood Immunization program had a common agenda globally. The goal was to achieve 80% of coverage of the 6 EPI vaccines for children. So different agencies brought what they could contribute including money, technical expertise and others to this common agenda. During the 1990’s this common agenda became fragmented and countries had to choose between doing polio eradication or adding new vaccines to the EPI vaccines or do health reform. The system began to decay. There was decreased donor support and interest, an aging cold chain, little training in human resource development and the end result was that coverage was declining. Many countries were unable to implement new vaccinations into a decaying program.

At the same time there was also a public health paradigm shift from child survival to health reform. Child survival focused on ways to improve the health of a child putting immunization at the top of the public health interventions. Health reform shifted emphasis from vertical programs (immunization) to a more horizontal approach to health care. The past 10 years however have shown us that this approach has actually caused a worsening health status for the world’s children especially in sub-Saharan Africa. More recently many countries are recognizing that the delivery programs such as immunization, malaria and TB control need attention and they need to reemphasize the program delivery piece again.

Several people who were concerned about this discrepancy formed the global alliance for vaccine and immunizations (GAVI). This organization and individuals involved with it have a deep belief in immunization. There is also a sense that a new common agenda can be forged and that immunization can be restored high on the global public health agenda. Resources need to be raised to see this happen but felt that this could be accomplished. The bedrock of the future is sustainable delivery infrastructure, sustainable financing, and sustainable human resources for capacity building.

This conceptualizes the GAVI network. At the center is the National Immunization Service in each country. Surrounding this is a network of partners such as the World Bank, WHO, UNICEF, and other foundations and non-governmental organizations. Included in this is the vaccine industry which includes the National Institute of Health, pharmaceutical and vaccine manufacturers and others. GAVI was proposing new way for the National Immunization Services and their partners to work together at national, regional and global levels. This is necessary to avoid any one agency or partner pushing its own agenda into a country and trying to avoid time, money and energy being wasted.

This slide shows the new working plan for how the organizations can work together with the country’s National Health System developing their priorities and then applying for funding which is then reviewed by a committee and sent to the "vaccine" funder to approve the application.

GAVI is part of this alliance and is not an actual organization; there are no GAVI offices and no officers. It is an alliance of partners working together to achieve a common goal.

GAVI has a regional working group and a task force working group to help coordinate the partners’ activity more effectively.

We asked the countries National Immunization Service to come up with a 5 year plan and coordinate this with the National ICC which includes a member from each of the organizations listed on this slide. The ICC then tried to come up with agreed upon goals and provide "real" technical and financing solutions. Each of the involved organizations were then tasked with doing their portion of the job to let the ICC and National Immunization Service realize its goals.

Here is a schematic of the planning process and the aspects that are needed including technical aspects and financial aspects. GAVI tried to make the system work through better coordination of the different agencies to realize the country’s 5 year plan. In order to actually realize this plan GAVI went to the Bill and Melinda Gates foundation which donated an initial gift of $750 million US over 5 years to start the project. With this initial investment, the GAVI organizers went to other countries and obtained additional financial commitments. The current fund now has approximately $1.4 billion US. The goal is to raise $1.8 billion US over 5 years.

There is a tiered approach to funding based in part on the countries capability and current immunization rates.

If they have the DTP 3 coverage of less than 50% they can apply for funds for immunization structure development. Finances for newer vaccines will not be incorporated until a country has achieved at least 50% coverage for the 6 basic EPI vaccines. Yellow fever vaccine and single use syringes are also supplied if needed. The new auto-disabled syringes were developed by PATH, these are single use syringes which cannot be reused and can therefore reduce injection mediated infections such as HIV.

If the DTP-3 coverage is between 50-80% then the country gets support for infrastructure strengthening plus newer vaccines such as hepatitis B, and Hemophilus influenza B (Hib), as well as yellow fever vaccine is applicable.

If a country has 80% immunization coverage, they receive the newer vaccines but do not receive infrastructure support as they likely do not need support for this. This is not entirely true and special projects have been developed for some countries who do need some infrastructure support.

The coverage rates are obtained from the central data that is presented to organizations like WHO and through vaccination surveys done by organizations like UNICEF. GAVI also does spot audits of the procedures for immunization and can show areas of high and lower coverage. The way the funding is set up; there is a disadvantage to overestimate your coverage so more countries have been able to provide more accurate vaccination coverage.

This map shows the 74 countries eligible to apply to GAVI and vaccine funds. So far 53 countries have been approved.

Our current goal is to focus on getting hepatitis B, Hemophilus influenza b, yellow fever and safe syringes to eligible countries. In 5-10 years to introduce newer vaccines such as pneumococcal, meningitis A, and Rota virus vaccine. The second focus is to on improving vaccine coverage, reduce vaccine waste and make vaccines 100% safe to give including safe syringes.

In summary, financial resources are available now to strengthen the immunization infrastructure, give hepatitis B and Hib vaccines and provide for safe injections for children in the 71 poorest countries in the world. We can give significant help with special programs in China, India and Indonesia. The challenge remains how to make this work programmatically as a whole and for the individual countries.

Study Questions:

What ethical and public health issues arise as the gap between developed and developing countries widens with respect to availability of new vaccines?
Describe how GAVI works and list 2 advantages and disadvantages.
What are the current components of the EPI 6 vaccines?