Perspectives in Health Magazine
The Magazine of the Pan American Health Organization
Special Centennial Edition
Volume 7, Number 1, 2002
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Perspectives in Health Magazine |
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Vaccines have helped us conquer some of humanity's worst scourges in the past century. In the future they will help us control and even eliminate many more.
It took 181 years from Edward Jenner's introduction of a smallpox vaccine for public health efforts to succeed in eradicating that disease from the globe. Even today, the gap between the introduction of a vaccine in the industrialized countries and its use in the poorer nations remains dauntingly long. Yet vaccines have proven themselves to be the most cost-effective public health tools in history.
How will progress in vaccines affect public health in the next 100 years? What lingering diseases will they help us conquer? How will their global use be financed? What lessons from experience can be applied to future vaccination campaigns?
If one had a crystal ball to look at the future of vaccines, it would no doubt reveal some important and heartening milestones, possibly including the following:
In reality, we can only speculate meaningfully on the future by thoroughly analyzing the past and present. Yet even in that real-life context, the prospects look bright indeed for a major impact of vaccines on global human health.
Smallpox is an important and encouraging case study. Though the vaccine has been around for more than two centuries, it took a mere 11 years for a disciplined campaign that was adequately financed and brilliantly led to achieve eradication. What came as an encore?
Just as smallpox was nearing eradication in the late 1970s, the World Health Organization (WHO) launched the Expanded Programme on Immunization (EPI), which included six infant vaccines: against diphtheria, pertussis, tetanus, poliomyelitis, measles and tuberculosis. Although EPI got off to a slow start, the concept of universal childhood immunization was embraced seriously from 1984 on.
As a result, global immunization of infants rose progressively to just under 80 percent coverage by 1990. This overall statistic, however, hides the fact that coverage was quite uneven. In countries with per capita GDP of less than $1,000, coverage reached a mean of just over 50 percent. In the Americas, coverage was much better (often spectacularly) than the global average.
Unfortunately, since 1990 no real further progress has occurred, and indeed coverage has slipped in a number of countries, with coverage in the poorest countries now at just over 40 percent. EPI has saved many millions of lives and must be counted as a success. Yet globally there are still at least 2 million vaccine-preventable deaths every year in children under 5.
Polio eradication
With the Americas once again in the lead, global polio eradication efforts began in earnest in 1988. It was soon realized that routine infant immunization, although essential, could not do the job alone. It was buttressed by three additional strategies: national immunization days (NID), a global system for surveillance, and "mop-up" operations, that is, intense vaccination efforts around the last few index cases.
National Immunization Days represented a huge effort in social mobilization, receiving extraordinary help from Rotary International, the news media, the government sector and, particularly, highly involved health ministries. On a single day, all of a country's children under 5 were lined up and given the oral Sabin vaccine. This succeeded in finding many hard-to-reach children who, for one reason or another, had not been caught in the routine immunization net.
As it turned out, it was necessary to have two NID a month apart, and to repeat the effort yearly for at least three years, turning Rotary's Polio Plus campaign into a monumental task. As polio gradually came under control, it became important to detect the residual cases. Therefore, a surveillance system was instituted to bring all cases of acute paralysis (technically termed flaccid to distinguish them from strokes) to the notice of health authorities. When cases were found, two stool samples were sent to accredited laboratories to see if the polio virus could be grown. This tedious but vital surveillance task has been absolutely crucial.
Finally, "mop-up" operations, consisting of dwelling-to-dwelling immunization around the last known cases, are the last step toward eradication. Thanks to this quadruple strategy, there have been no indigenous wild polio cases in the Western Hemisphere since 1991, none in the Western Pacific Region since 1997, and none in the European Region since 1998. Even in India, wild polio is now essentially confined to two northern states.
Over the next couple of years, WHO will be concentrating on 10 countries in Africa and South Asia, five of which are conflict ridden and five others "reservoir countries" because of high population density and very poor living standards. The target year for the global eradication of the wild polio virus is 2005.
Although the Polio Plus campaign is a vertical program (as opposed to horizontal programs, which seek to provide primary health care across a broad front), it has broader implications. First, in many cases vitamin A supplements are administered simultaneously. Second, it provides a contact point between remote and disadvantaged rural poor and national health systems, often leading to a greater awareness of other available health interventions.
Global alliance
The experiences of both smallpox and polio show the extraordinary power of the vaccine approach. But what about the present state of play? In 1998, there was a sense that new energies were needed in global immunization efforts. Donor interest in EPI was fading, the vaccine infrastructure in many countries was deteriorating, and research was lagging on new vaccines for diseases occurring only in poor countries.
But as WHO, UNICEF, the World Bank and leading academics were searching for a new dynamic, help came from an unexpected source: William H. Gates III and his wife, Melinda French Gates. The Gates Foundation made an initial pledge of $100 million to a Children's Vaccine Program, at first designed to determine and overcome the chief roadblocks to the introduction of important new vaccines into the EPI. Within two years, the Gates' extraordinary generosity had led to a total of $1.4 billion com-mitted to vaccine-related projects, including considerable research and development funds and a $750 million gift earmarked for a Global Fund for Children s Vaccines, administered by UNICEF. The Vaccine Fund, as it is now known, targets the 74 poorest countries in the world, namely, those with per capita GDP of less than $1,000 per annum. Several countries have added pledges to the fund, and it now stands at more than $1 billion.
After extensive consultation with all stakeholders, the Global Alliance for Vaccines and Immunization (GAVI) was launched in 2000 as an unincorporated alliance of WHO, UNICEF, the World Bank, the Gates and Rockefeller foundations, and other nongovernmental organizations, along with bilateral donors, developing country health authorities and vaccine manufacturers from both developed and developing countries.
The GAVI board was chaired initially by WHO Director-General Gro Harlem Brundtland and is now chaired by Ms. Carol Bellamy, executive director of UNICEF, ensuring commitment of their respective organizations at the highest level.
GAVI has set itself three major goals. The first is to improve infrastructure for immunization in countries where it is inferior through cash grants dependent on a demonstrable increase in vaccination coverage.
The second is to purchase, for selected countries, vaccines beyond the traditional six, primarily hepatitis B, yellow fever and Hemophilus influenzae B, or Hib, for meningitis, pneumonia and septicemia.
The third and longer-term goal is to do applied research and development work for newer vaccines already well down the track, such as against pneumococcus and rotavirus. Already two-thirds of GAVI s target countries have grants and/or vaccine supplies flowing to them. Yet sustainability is a real worry, as the beneficiary countries will gradually have to subsume the costs of the vaccines into their own health budgets.
Future vaccines
Despite the amazing progress of immunological science, there are many diseases for which we do not yet have an effective vaccine. We could see rapid progress in the so-called "low-hanging fruit," those vaccines-in-research whose underlying principles have largely been established and that seem to require relatively straightforward development work to become available. This is probably the case for the A subtype of meningococcus, responsible for horrible meningitis epidemics in sub-Saharan Africa; for rotavirus, an important cause of infantile diarrhea; and for pneumococcus, which will involve major expense because each of many different disease-causing types will need to be included in an eventual vaccine.
It would be surprising if vaccines for these pathogens were not available within five to seven years. Again, we must seek public sector funds for their early introduction.
Somewhat more speculative are vaccines against shigellosis, or bacillary dysentery, a cause of some 800,000 deaths per year, nearly all in very poor countries; and against Helicobacter pylori, the cause of peptic ulcer disease, chronic gastritis and a big proportion of gastric cancers. It is doubtful whether the pharmaceutical industry will come up with sufficient research funding to drive these vaccines all the way to registration. The chances are better for a vaccine against human papilloma virus (HPV), the cause of cervical cancer and genital warts, because industrialized countries have a major interest in preventing these problems.
From a public health viewpoint, there are three "future vaccines" of even greater interest: those against HIV/AIDS, malaria and tuberculosis. These are so important that each deserves some discussion. So far, an AIDS vaccine has eluded us, primarily because the human immunodeficiency virus has such devilishly clever tricks up its sleeve to foil the host's natural defense system. It chooses to live in and destroy one of the most important cells of the immune system, the so-called CD4+, or helper T cell. It also infects scavenger cells important in initiating immune responses. It can go underground in these cells, only to emerge much later. Being an RNA (ribonucleic acid) virus, it is subject to a very high rate of mutation, so that when the immune system does manage to polish off most of the virus, a mutant form with a different antigenic signature pops up, needing to be dealt with in turn. Finally, the active recognition sites on the grappling hooks that the virus uses to hang onto its target cell are skillfully hidden from the prying eyes of antibody molecules until the very moment of docking and entry.
Despite these challenges, progress is being made toward a vaccine. Stratagems have been devised to evoke antibodies that are broadly active against different subtypes of the virus. During the long latent period of the disease, while the patient is still well, the body's killer T cells do fight against the virus, keeping the total load in the body relatively low. If a vaccine can provoke those T cells into intense activity before infection occurs, the very small virus load entering the body might be destroyed completely.
We have good ideas about how to craft such a vaccine; it is now necessary to trial these one by one in the clinic, a process that is necessarily very slow. An alliance known as the International AIDS Vaccine Initiative (IAVI) has raised sizable funds to speed clinical trials, so that several different vaccine candidates can be assessed simultaneously. Much of this trial work will have to be conducted in developing countries, given their higher incidence of infection.
Targeting malaria
Malaria is the worst of the human parasitic diseases, killing between 1 million and 2 million people every year, chiefly in Africa. People living in endemic areas eventually develop partial immunity, such that they do not get attacks despite having parasites in their blood. If they move to a non-malarial area for several years, they gradually lose their immunity.
Here, scientists will have to do better than nature.
There are four susceptible points in the parasite's life cycle when it may be vulnerable. First, a motile form known as a sporozoite is introduced into the skin by the night-feeding female Anopheles mosquito. Within less than half an hour, sporozoites reach and enter liver cells. Up to that point, antibodies directed to the sporozoite surface might lead to their destruction. Once in the liver, the parasite multiplies, during the process shedding bits that will reach the surface of the cell. If a killer T cell recognizes these bits (called peptides or T cell epitopes), the affected liver cell is attacked and destroyed before it can release its progeny into the bloodstream. Infection is thus aborted.
But once the progeny (known as merozoites) are in the blood, they quickly attach to and infect red blood cells. They then multiply, rupture the red cell, and enter a new one. It is this blood-stage cycle that is responsible for the symptoms of the disease. In its transit from one red cell to the next, the merozoite is briefly susceptible to antibody.
Finally, some merozoite-infected red cells release gametocytes, sexual forms of the parasite, which can mature within the mosquito into male and female gametes. When these unite, the life cycle is completed. If one were to make antibodies to these gametocytes, one would not help the patient, but at a population level, transmission would be blocked, and eventually the disease might be brought under control.
Experimental vaccines incorporating each of these four sets of ideas have been shown to work in model systems. It is now a question of subjecting them to phased human trials. One of the many Gates Foundation programs, the Malaria Vaccine Initiative, is planning to do just that. So far, some partial success has been achieved in human trials with a sporozoite vaccine and a combination blood-stage antigen vaccine.
Attacking TB
Why do we need a tuberculosis vaccine other than the BCG (Bacillus Calmette- Guerin) vaccine? Simply because this live, attenuated bacterium can protect infants from tuberculosis but appears incapable of coping with the real problem, namely, pulmonary tuberculosis in adolescents and young adults. Though not as far advanced as it is for AIDS and malaria, research toward a new TB vaccine is exploring plenty of bright ideas, including both live attenuated and molecular approaches. A recently completed tubercle bacillus genome project is speeding the search. One of the biggest problems, not only with the "big three" but also with other vaccines, is the fact that pure protein molecules made by genetic engineering do not by themselves induce a strong immune response. For this we need immune-strengthening substances called adjuvants. Many are under development, but these tend to be toxic, and the search for more satisfactory adjuvants is intense.
Alternatively, we need new and craftier ways of delivering the vaccine. For example, we can take the gene for an important vaccine molecule (or antigen) and transplant it into a virus, then inject that virus, which will strongly alert the immune system. We can also inject DNA coding for antigens, which enters cells and then creates a factory where the body itself is manufacturing vaccine molecules over a considerable period. One highly promising strategy is known as prime-boost, in which a DNA vaccine is injected first and an engineered virus next. This has worked well in animal models of both HIV/AIDS and malaria.
Genomics has opened up other entirely new avenues as well. Plants can be engineered to produce antigens, so an edible vaccine is feasible. This would have to be constructed so that either a mucosal adjuvant or some other immune-enhancing factor was also present. Vaccines can also be applied to the skin and, amazingly, find their way into the body, yielding a transdermal vaccine. Here again, immune enhancers will represent the problem area.
Within a 100-year timeframe, many of these ideas will seem clumsy; third and fourth generation developments will then be in use. Special attention will have to be given to noninjectable vaccines--no one wants their babies to become pincushions.
Vaccine combinations will become increasingly important. Some companies are already working on a sevenvalent vaccine against diphtheria, pertussis, tetanus, poliomyelitis, hepatitis B, Hib and meningococcus C all mixed together. A measles-mumps-rubella-chickenpox vaccine is already on the horizon. There is little doubt that a century from now, infants will be protected against most of today's most prevalent infectious diseases and even more.
How many of these diseases will we eradicate completely? The Pan American Health Organization has targeted measles as the next one for the Americas and has already made tremendous progress toward that goal. Given the problems encountered with polio eradication efforts in Africa and South Asia, global control of measles may be more realistic than total eradication. In principle, however, any microorganism against which there is a highly effective vaccine, which has no animal reservoir, and which (unlike tetanus and anthrax) does not persist long term in soil or water, is eradicable.
The two major challenges are cost and the fact that an organism against which infants are not being immunized because it has been eradicated, such as smallpox, could be used for bioterrorism. Short of eradication, it is encouraging to note how rapidly a disease can be brought under control. For example, in Taiwan the widespread use of hepatitis B vaccine has dramatically lowered the carrier rate and has already diminished the incidence of liver cancer in relevant cohorts.
A golden century?
In a world sobered by the events of Sept. 11, 2001, it is no longer naïve to hope that grave social inequities around the globe will finally receive the attention they deserve. There is growing recognition that a reservoir of communicable disease in any country represents a global threat, given the extent of international travel. Prevention of infection is not only better than cure, it is much cheaper.
Yet for the splendid examples of Rotary International and Bill and Melinda Gates to be followed more extensively, one additional realization is needed. That is the nexus between health and economic development. In the words of Harvard economist Jeffrey D. Sachs and his colleagues: "The linkages of health to poverty reduction and to long-term economic growth are powerful, much stronger than is generally understood. The burden of disease in some low-income regions stands as a stark barrier to economic growth."
Sachs estimates that $30 billion per year of additional donor support could save 8 million lives each year and provide direct economic benefits of $186 billion per year. Over the next 100 years, that adds up to truly astounding progress for the human race. As far as vaccines are concerned, the long journey from Edward Jenner to William H. Gates III would then have represented only the beginning of a golden era in public health.
