Vaccine Initiatives and Updates

Table of Contents

History of Vaccination
Lists of Old and Newer Vaccines:

Currently Available

Available Soon

Future

Malaria Vaccine
Introduction to New Vaccines
Example of Hepatitis B Vaccine
Gaps in Immunization
GAVI Vaccine Projects: Where do we go from here?

Student Questions

Readings

History of Vaccination

I think it is important to understand the history of vaccinologies, starting with Jenner through Louis Pasteur. Before the extended program on immunization (EPI), vaccines primarily benefited children in the industrial world. Before the EPI started in the early 1970's only about 5% of the children in the world were getting routine immunizations. Since 1990, vaccines reach about 80% of the world's children. I consider this to be the greatest public health achievement in history, and I think that we need to extend this to the newer vaccines that are becoming available.

[Expanded programme on immunization coverage.]

The graph shows data from 1977 to 1990, where coverage initially in the world was about 5 to 10% and by 1990, 80% had basic immunization. This was 80% coverage with six basic antigens: polio, measles, DTP, and BCG. Since 1990, the coverage has stagnated and actually fallen from about 80% to about 75%. In addition, some important new vaccines like hepatitis-B vaccine and Hemophilus influenza-B vaccine have been very slow to be introduced into the developing world, even though they have been introduced into the industrial world.

The world is very unevenly distributed vis-à-vis that 80% coverage, but actually most of the world, with the exception of sub-Saharan Africa, had about 80% coverage. The actual coverage in 1996 [Global reported immunization coverage with three doses of DTP in infants, 1996.] in sub-Saharan Africa shown in red was below 50%, and most of the other countries in sub-Saharan Africa were 50 to 80%.

I believe that with sanitation, immunization is medicine's greatest and most cost-effective benefit to mankind. I think we need to realize that the greatest potential immunization has to offer mankind, is not yet realized. The vaccines against the eight EPI diseases-that is the six basic antigens plus hepatitis-B and yellow fever could potentially prevent 7 million deaths per year. New vaccines have the potential to prevent an additional 15 million deaths per year.

[Deaths from potentially vaccine preventable diseases.]

This graphic shows the potential of immunization. On the left, we have small pox which used to kill about 5 million people per year and has been eradicated from the world. The EPI plus target diseases: polio, diphtheria, pertussis, measles, neonatal tetanus, hepatitis-B, BCG, and yellow fever, have great potential, but more needs to be done for control of these diseases. In the case of DPT, measles and tetanus, it is an access problem. The current vaccines are good, and if we could reach all the children that need them, we could do the job. Tuberculosis is another matter. BCG is not a very good vaccine at preventing TB infection and can only prevent a tiny fraction of tuberculosis.

We see that not much has been achieved in diarrheal and enteric disease. A very effective rotavirus vaccine was put on the market in the United States but had to be withdrawn because of the side effect of intussusceptions. There are typhoid and cholera vaccines that are fairly effective, but they have mainly been used for travelers from industrial countries.

In terms of acute respiratory infections, Hemophilus influenza-B vaccine (Hib) is an incredible vaccine. It eliminates the disease not only in the people who get the vaccine but also their brothers and sisters who never got the vaccine. It is extraordinarily rare to see even one case of Hemophilus influenza-B disease in places where the vaccine has good coverage. Nevertheless, the penetration of Hib vaccine into the developing world has been very low. A new vaccine against Streptococcal pneumonia has been licensed in the United States. It is a nine valent vaccine that is designed for the industrial world. An eleven valent vaccine with additional subtypes that will allow their use in the developing world are in clinical trials now. We at the Bill and Melinda Gates Children's Vaccine Program are involved in that.

Vaccines against malaria and other parasites have not yet been developed. This science is extremely difficult, as is the science in developing an HIV vaccine. But we have to think about the use of malaria vaccines, schistosomiasis vaccines and even HIV vaccines in the context of the reality that I am going to be talking about, which is access and delivery. If we had a malaria and AIDS vaccine tomorrow, we would not be very effective in getting it to the people in the world that need it the most. The people who develop these vaccines do not really understand that. They think that once you develop a vaccine and it looks good in the lab and in clinical trials, that it is going to get into people's arms, and that is very far from the truth.

At the same time we were developing our ability in the world to deliver vaccines to many of the people in the world, there was a revolution in biotechnology that started to bring us more and more impressive antigens. Basically, vaccinology starts with a pathogen. The classical way to make vaccines was to either inactivate or attenuate the pathogen or some part of the pathogen, for example a toxin. So most of the vaccines that we use actually have been produced by the classical pathways of inactivation or attenuation.

With the discovery of DNA, nucleic acid, and with the ability to do molecular cloning, an entire spectrum of new ways to make vaccines unfolded in very exciting ways. For example, you can express subunits of a pathogen. You can put the gene that makes hepatitis-B surface antigen into yeast, grow the yeast, and now the yeast has the surface antigen gene, it thinks that it is supposed to make hepatitis-B surface antigen. That can be purified into a subunit vaccine, for example the hepatitis-B vaccine. You can also, using similar techniques, make peptide vaccines. You can insert genes into other vectors. You can, for example, put into Vaccinia almost any other gene that you want. Or you could put, for example, hepatitis-B surface antigen into salmonella. Then you can attenuate the salmonella so that it is not pathogenic, but it grows and attempts to make oral hepatitis-B vaccines by inserting the surface antigen gene into salmonella. Those are being experimented with.

You can mutate genes very selectively. Originally with attenuation, it was an empirical attenuation. You attenuated an organism, and then you tried it out in animal models or sometimes even people, and you found out that it was underattenuated, and they got sick, or it was overattenuated, and the vaccine did not work. Now you can selectively discover which genes actually cause the pathology that you are interested in, produce a toxin or whatever effect is detrimental, and you can selectively change those genes and make live attenuated vaccines where the mutogenesis was done very selectively. Or you can take this nucleic acid, and you can make it into a little plasmid and use it by itself as a vaccine, and that is the very exciting area of nucleic acid vaccines, which a lot of people think is the future of vaccinology.

Currently available as global vaccines are hepatitis-B in various combinations with DTP, Hib, rubella, mumps, hepatitis-A and varicella. For limited use would be yellow fever, typhoid, cholera, Japanese encephalitis, rabies, pneumococcal, and meningococcal vaccines. These are currently available. Available soon, will be improved, influenza and rotavirus vaccines.

Streptococcal pneumonia vaccine is conjugated. Conjugation technology is a new technology that has recently been introduced. Polysaccharides in general are not immunogenic in people less than two years of age, but by conjugating a polysaccharide to a small carrier protein, like tetanus toxoid, you can make these polysaccharide chains immunogenic, even in infants. By applying this conjugation technology to Hemophilus influenza-B, Streptococcus pneumonia and meningococcal polysaccharides, you can now make vaccines immunogenic in very young children.

Lists of old and newer vaccines:

There are groups working on newer vaccines, such as respiratory syncitial virus (RSV), which is a major cause of respiratory morbidity around the world. A number of years ago, when the first RSV vaccine was introduced, the vaccine did not prevent RSV and the RSV that children got was enhanced. There were several deaths, and the vaccine makers had to go back to the drawing board.

What we need to do is try to influence the availability of these vaccines in developing countries. We also want to shorten the time of introduction into the developing world. If you think about hepatitis-B vaccine, it became commercially available in 1982, and it is only in the past five years that there has been significant penetration of that vaccine into the developing world.

The other major problem is to encourage the development of antigens of less commercial interest. If you think about the vaccines that are currently available, all of them were developed because there was a significant market in the industrial world. We were fortunate that these same pathogens were major pathogens in the developing world. So the pharmaceutical companies make their money by selling vaccines in the United States and Europe, then these vaccines trickle down into the developing world. But if you take a pathogen of enormous importance, for example malaria, that does not have a significant market in the industrial world except maybe the traveler's market. You will find that industry is not interested in investing huge amounts of money they would need to develop that vaccine.

We have to make sure that studies are done to address important issues early in the research and development of a vaccine. For example, when the Hib vaccine became available, early surveillance showed it was extremely effective. When they finally did a burden of disease study for Hemophilus influenza there was very little data available. The worldwide prevalence of this disease was unknown. Therefore it was unknown if the vaccine should be globally used or used as region specific.

We have to try to impact the affordability of vaccines. The new pneumococcal vaccine costs approximately $68 per dose, and you need four doses. These kinds of prices are out of consideration for use of these vaccines in the developing world. We have to develop new pricing structures that allow us to get these vaccines an affordable way for the developing world.

Malaria Vaccine

The Gates Foundation has granted $50 million to establish a Malaria Vaccine Initiative. One of the solutions that they were looking for is to go to places like India and get them involved in producing promising antigens for phase I and II trials. Most developing country vaccine producers are not viable business operations at this time and certainly do not have the resources to move into the future with new high tech vaccines. Most vaccine production and the know-how to make and develop vaccines has shifted over into the private sector. Within the private sector, there are increasing mergers. What this means is that there are four companies in the world that have the resources to make vaccines. We have to adjust to that reality. It is a very dangerous reality.

Vaccine business, in the larger picture of the pharmaceutical industry, is a tiny piece. It is a piece that might represent 5% of their business but give them 25% of their liability and 40% of their headaches. Business people are saying all the time within these companies, get rid of it! Why are we doing this? It is only really the dedication of these people within the companies that want to make vaccines who so far have won the day. We are in real danger in the future of ending up with only two companies in the world that know how to make vaccines. Their internal policies, driven by their economic needs, will dictate what vaccines become available and at what price. This is a real threat to the future.

Introduction of New Vaccines

During the 1970s and 1980s, most of the energy that went into immunization was building a delivery infrastructure using the six traditional EPI vaccines. These vaccines are all older vaccines in the public domain, and cost pennies per dose. There was little interest in the newer antigens like hepatitis-B vaccine. It was not a child survival issue. It took nearly a decade to convince UNICEF that this had to do with children being infected early in life.

The newer vaccines that came along were more expensive. Why were they more expensive? First of all, they were protected intellectual property. There were patents on them, they were much higher tech, and were much more expensive to produce. You have to realize that to produce a new vaccine from early research and development through license, clinical trials, and marketing it costs in the range of $200 million. You may agree with capitalism and free markets or you may not, but the reality is that that seems to have emerged as the dominant economic model in this world. These companies who invest $200 million need to get their money back. The current financial infrastructure underlying immunization is incapable of supporting new vaccines.

The six traditional vaccines cost about 70 cents per child. That is, 70 cents U.S. buys a dose of BCG, three doses of OPV, three doses of DTP, and a dose of measles vaccine. UNICEF spends less than $100 million to buy about a billion doses of these vaccines. These older vaccines are very affordable. So even at 70 cents per dose, a new vaccine could triple the cost of what we spend on the vaccines. The pneumococcal vaccine could cost 10 times this amount.

Another issue was that the EPI had other priorities. They had to eradicate polio, they had a target for control of measles, they wanted to eliminate neonatal tetanus, and they wanted to raise global immunization coverage to 90%. These new vaccines competed for scarce human and financial resources at all levels. What we were doing was taking an extremely understaffed, overburdened, undertrained immunization program in a developing country and making impossible demands on these people. We needed to come up with a strategy to shift the current paradigm. Vaccines, even at a dollar or more per dose are still one of the most cost-effective strategies in all of medicine. We need to get governments, vaccine producers and distributors to realize it is worth the investment. There is also a feeling that the industrialized world should be solely responsible for immunizing the world's population. It is important to have all countries buy into the notion that each countries government is responsible for their children's immunizations.

There are a lot of unanswered questions that need to be answered before we can introduce new vaccines. We have to understand the burden of disease. We need to understand the characteristics and potential impact of the vaccine and the perception of the priority of its control. We also need to study the impact of the vaccine on the program, the cost-effectiveness, affordability, supply and quality issues.

Example of Hepatitis B Vaccine

[Geographic pattern of Hepatitis B prevalence.]

This slide shows the global prevalence of hepatitis B. Some regions, in red, have prevalence rates greater than 8% of the population. In high endemic areas hepatitis B is primarily a disease that is transmitted among very young children or from mother to child. In North America and western Europe, it is primarily a disease of high risk groups such as intravenous drug users and healthcare workers exposed to the virus. In order to control hepatitis-B, we have to think about different strategies for different parts of the world. The only strategy that is actually effective in controlling hepatitis-B is universal immunization of children, adolescents or both.

How important is hepatitis B? Two thousand million people have markers showing that they have current or past infection. There are 350 million chronic carriers in the world. About a quarter of them will die from chronic liver disease, either cirrhosis or liver cancer. It kills about a million people per year. It is now 85 to 90% vaccine preventable. This is one of the major diseases in the world.

[Cancer rates, Gambian males 1986-96.]

These are cancer rates in males in Gambia, West Africa. The upper line shows all cancer deaths, and the lower line shows liver cancer deaths. Liver cancer due to hepatitis-B is the number one cause of cancer death for men in Gambia and usually the number two cause of cancer death for men in Asia.

In 1991 the EPI and in 1992 the World Health Assembly recommended that all countries introduce hepatitis-B vaccination by 1997. This was a major political step in the world to happen. When we studied the impact of this vaccination on populations we found that many people lost the Hepatitis B surface antibody but seemed to retain immunity against the disease. There was no disease and extremely rare reports of carriers in infants who had responded to the vaccine. Originally, we thought that it was the antibody that was protecting people in this vaccine. Now we know that the long-term protection afforded by the vaccine is provided by immune memory cells.

The other thing we learned is we were able to reduce the carrier prevalence from 10-15% to low endemnicity of less than 1% in immunized cohorts of children. We can also lower liver cancer rates in countries that have high immunization rates.

[HBsAg carriers before and after immunization, Shanghai.]

This is an example from Shanghai, China before immunization in 1984 compared to 1994 after immunization. Less than 1% of the children in Shanghai are now carriers of hepatitis-B since immunization began.

[HBSAG prevalence and post HB immunization.]

This slide shows the global impact on carrier status before and after immunization.

By 1999, we were successful in getting hepatitis-B vaccine into 110 countries, most of them developing countries. The places that have not yet used the vaccine are primarily in sub-Saharan Africa and the Indian subcontinent. When we looked at countries that had high coverage by their economic status we found that countries who had a GNP per capita of more than $500 were using the vaccine, and almost none of the countries less than $500 were using it.

What can we do about economic disparity? We conceptualized the globalization structure as partners, supporting national immunization services in countries. We call this the World Immunization Network (WIN). [World Immunization Network]
The World Bank, WHO, UNICEF, academic institutions, industry and technical organizations and NGOs exist, in terms of immunization, to support the national immunization services within a country.

Gaps in Immunization

Three primary problems have been identified with global immunizations.

1. Stagnant growth in immunization over a decade with a decline in basic EPI coverage for certain countries as well as marked regional discrepancies. There are still 25 million children in the world that do not get any vaccines at all.
2. Lack of introduction of newly-developed and efficacious vaccines against major child killers to children in the poorer, developing countries.
3. Limited investment into vaccine research for diseases with high burden in developing countries in preference for diseases in developed countries with lesser global public health importance but higher market-value.

To help problem solve these issues we created two new structures: Global Alliance for Vaccines and Immunization (GAVI), and Global Fund for Children's Vaccines. This is an attempt to renew interest and financial support for immunization.

GAVI and the Global Fund for Children's Vaccines recognize that improvements need to be made in the vaccine delivery infrastructure, the financial tools available to the poorest developing countries, and the resources available for research and development for vaccines primarily of use in developing countries. GAVI and The Fund propose a new way for National Immunization Services and the partners in development which support them to work together at national, regional and global levels.

The GAVI partners are the Rockefeller Foundation, UNICEF, World Bank, WHO and the Bill and Melinda Gates Children's Vaccine Program. At a global level, it consists of a board, task forces, and other representation. [Global Alliance for Vaccines and Immunization] Most importantly this is happening at the country level. For each developing country, you have a national immunization service. In that country you also have the World Bank, WHO, UNICEF, USAID or Canadian or Italian representatives. It differs in each country. What you have is a situation where the government negotiates independently with each of these agencies, and each of these agencies pushes their own agenda. What we are trying to do, in the area of immunization, is to get all these people giving the same message to the government. We would like to coordinate the interaction between the national immunization system and the donors by forming a national immunization coordinating committee (NICE). [National Interagency Coordinating Committee] This committee would agree upon common goals, provide real technical solutions (i.e. money), and each agency would bring to the table what it has to offer.

The goal is that through GAVI and the global fund, each country will form a national immunization coordinating committee and produce a multi-year, comprehensive immunization plan in concert with all of the partners. Then that plan would have technical and financial aspects. We use the financing mechanisms in a coordinated way to support that one plan instead of independent negotiations. This would reduce some of the corruption patterns that can occur. It can also maximize the countries own contribution and work with other contributors as well.

As a starting out point, we went to Bill and Melinda Gates Foundation and convinced them that this was important, and they gave us a gift of $750 million. The fund will eventually have three separate sub-accounts:

1. for procurement of newer vaccines and safe injection equipment;
2. for access and infrastructure; and
3. for research and development of new vaccines.

[Operation of the new vaccines window.]

Here is a schematic of how this new operation system will be designed to function. Each part is dependent on all participants working together for success. The countries form a national immunization coordinating committee. That committee, with the government, produces a multi-year immunization plan and use all the financing resources, including the funds. The countries make an application to the Global Alliance, the fund buys them vaccine, and, in the future, there will be monies available to work on access and infrastructure.

What we need to do to fulfill our mission is to promote equal access to new, life-saving vaccines and to increase the political will. We have to raise immunization to the highest levels on the political public health agenda. A high level meeting including heads of WHO, UNICEF, and the Bill and Melinda Gates Foundation, among others, has met to launch this project. We have succeeded both in raising immunization to the highest levels politically on the global public health agenda, and have been able to help define new financing solutions by creating the global fund. We are working to provide stronger immunization services at all levels through this program and obtain key information that is needed to make decisions in the future and develop new technologies.

GAVI Vaccine Projects: Where do we go from here?

Hepatitis-B is the vaccine that most countries will want to introduce first through the GAVI fund process. We will learn how we can make this process work by working with the hepatitis-B vaccine. With hemophilus influenza B (Hib), we are supporting burden of disease trials in Asia and many parts of the world. With pneumococcal vaccine, we are supporting trials in the Gambia and the Philippines using the new conjugate pneumococcal vaccines that are designed for the developing world. We are working to develop new technologies for the future with PATH. The auto-disposable syringe, which is a single-use syringe, was developed at PATH and is used widely around the world now. We are interested in developing more stable vaccines by something called the "Sugar project." By drying vaccines in certain sugars, we can eliminate the need for refrigeration and the need for the cold chain.

Student Questions

Q: What structures do you have in place to guarantee that the money is not being pocketed and the vaccines are still being brought and distributed to the people in need?

A: First of all, we send them the vaccines, not the money, and vaccine coverage is more or less well monitored in most developing countries. If we send them hepatitis-B vaccine, unlike essential drugs, most vaccines do not have additional value. They do not tend to get stolen and sold on the market, because there is no market for polio vaccine in a developing country situation. In general, have not had that problem with immunizations. Immunization coverage is monitored, both by routine system and by periodic surveys in various countries. It will be much more difficult to monitor infrastructure and access issues. One way we may do that is not to send the money to the countries, but to work through the partners and only fund things that we believe will be well monitored.

Q: Different companies have managed to get their products into remote areas of the world, such as cigarettes, Coca-Cola, etc. and I am wondering what strategies they use and why are health facilities less able to do that?

A: If you ask these companies, they would say that when you ask governments to do things, they do not do them very efficiently compared to what the private sector can do if there are proper profit motives in place. I think in a sense, they are right. If you go to the remotest place in the world and buy something with your credit card, chances are a month or two later you are going to see that purchase on your credit card bill. The private sector does have the ability to work at a precision that is kind of unheard of in their culture and through their governments. Nevertheless, we cannot depend on private sector delivering vaccines in the developing world. Fidel Castro came to Geneva last year and spoke at the World Health Assembly, and basically he said, "If you think that the free market is going to deliver healthcare to the poorest people in the world, you are very deluded." We have to work with the public sector and strengthen it to do this delivery, because the private sector is not going to deliver these vaccines, even if they produce them for us.

Readings:

Kane MA. "Status of hepatitis B immunization programmes in 1998." Vaccine, 1998 Nov; 16 Suppl: S104-8.

Simonsen L, Kane A, Lloyd J, Zaffran M, Kane M. "Unsafe injections in the developing world and transmission of bloodborne pathogens: a review." Bull World Health Organ, 1999; 77(10): 789-800.

Maynard JE, Kane MA, Hadler SC. "Global control of hepatitis B through vaccination: role of hepatitis B vaccine in the Expanded Programme on Immunization." Rev Infect Dis, 1989 May-Jun; 11 Suppl 3: S574-8.

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