Disease Surveillance
The Economics
of Vaccine Development and Program Implementation
Eradication
Vaccine
Supply, Saftey, Quality, and Delivery
Increased
Resistance to Antibiotic Drug Therapies
Ethics
of Clinical Trials in Developing Countries
Additional
Links
vaccination in Somalia, http://www.who.org
Worldwide epidemiological data provides important information on the urgency of the development of certain vaccines, in addition to providing information about the ideal characteristics of a potential vaccine. Collecting accurate and comprehensive data is often difficult, however, especially in developing countries, where the disease burden is also the largest. Nonetheless, surveillance data is critical for vaccine development and ideally, information on the incidence (for acute diseases) or prevalence (for chronic diseases), the predominant serotypes and subtypes, and antimicrobial resistance can guide allocation of resources for vaccine development (1). Rotavirus provides one example of the usefulness of disease surveillance in vaccine development.
After a vaccine has been tested and approved
for widespread use, and an immunization program has been implemented, a
disease surveillance program can be used to identify the so-called ìweak
linksî in the program. In particular, research initiatives should
address the reasons for nonvaccination or incomplete vaccination.
Four crucial questions, which have been previously identified, are as follows:
1) Is the present vaccination system inadequate?
2) Do the unvaccinated children and their
families have special characteristics that can help identify them?
3) Do parents lack accurate information?
4) Do unfavorable attitudes among communities
and families outweigh a good vaccination system and good information?(2)
Data sources may include data from health centers, direct observation of vaccination practices, conversations with experienced health workers, and community discussions. Supplementary studies can be designed to answer additional questions. (2) The components of one extremely successful disease surveillance system in India included ìsimplicity of the reporting procedure, low budget, private sector participation, personal rapport with people in the network, regular feedback of information through a monthly bulletin, and the visible interventions consequent upon reporting.î(3)
When an immunization program works well, health care workers are able to shift their attention from increasing vaccine coverage to controlling or eliminating the disease. It is at this point that disease surveillance becomes particularly critical. For instance, surveillance was crucial in smallpox eradication and poliomyelitis elimination in the Americas (4). The World Health Organization has also published a comprehensive review of the usefulness of disease and immunization program surveillance for control and elimination of measles. (5)
www.cdc.gov/nip/vacsafe/research/epimeth.htm
The Economics of Vaccine Development and Program Implementation
Vaccines are considered to be one of the most cost effective public health prevention strategies. Strikingly, there are many cases where the promise of saving money can create the political will for vaccine development, even when the promise of saving lives can not. For instance, the large amount of resources allocated to rotavirus vaccine development in the United States is largely a result of epidemiological studies that demonstrated the cost-effectiveness of reducing rotavirus related hospitalization. (6)
Cost-effectiveness studies can help health care program directors and government leaders in developing countries manage their resources and compare different operational strategies (7). Reports such as the World Bank World Development Report ìInvesting in Healthî can help quantify the ways a successful vaccination program will benefit society. This 1993 report showed the cost effectiveness of different interventions in terms of each disability-adjusted life year (DALY) gained. A DALY reflects the global burden of disease and the effectiveness of health interventions. It is defined as ìthe present value of the future years of disability-free life lost because of premature death or disability in a given yearî. (8) For measles immunization estimated costs were less then $10 per DALY gained or about $300 per death averted. (9)
The economic considerations of drug manufacturers and scientists often influence their vaccine development priorities. Because vaccines must be produced in large volumes, and offer a relatively low profit per dose, (10) pharmaceutical companies do not see vaccines as a profitable project. The fact that the largest markets for many vaccines are in developing countries, where the resources to purchase vaccines are limited, only worsens this problem. Public health officials from developing countries who were participants at the Harvard AIDS institute symposium on AIDS vaccines agreed that an ideal vaccine would require no more than three doses and cost $1 per dose. A useful vaccine could cost up to $10, participants said, but $30 per dose would be too expensive. (11) In contrast, therapeutic drugs are low volume high profit items. As of 1998, the new antiretroviral drug therapies cost between $12,000-15,000 per patient, per year. (12) Even for the most socially conscious companies, vaccine development is often seen as a way to loose money. (13)
In light of this perception, pharmaceutical companies and the western governments have preferentially targeted vaccines for diseases and subtypes that occur in industrialized countries. There are, however, some creative solutions to these economic concerns. For instance, it has been suggested that a company who has developed an internationally beneficial vaccine could donate the patent to an international organization in exchange for a patent extension of a drug of its choice in the industrialized world.(14) In addition, comprehensive cost analysis can demonstrate to industrial countries that their participation in global eradication programs will be cost effective in the long run. (15) For instance, the smallpox eradication campaign was completed at a total cost of $300 million dollars, while its overall economic benefit has been roughly $1000 million dollars annually. (16)
Another creative solution is the development of a two tiered pricing system, in which industrialized countries subsidize the distribution of the vaccine in developing countries. (17) Ideally once the manufacturer increases production efficiency, reduces production cost and begins to see revenues, the vaccine price will dramatically drop. (18) This process can often take an excruciating amount of time, however. In the case of the Haemophilis influenzea type b, the vaccine cost more than $20 at its introduction, and did not drop to the globally useful price of $1 to $2 for over 8 years. (18)
Complete global eradication of smallpox was achieved through a massive
immunization program implemented by the World Health Organization, and
announced in 1979. (19) It is a story full of suspense and intrigue,
which both raises hopes for poliomyelitis and measles eradication today
and provides a practical model for how this eradication could take place.
In Merka town, Somalia in 1977, Ali Maalin (see picture below) was the
last recorded case of smallpox in the world. At the onset of his
smallpox rash, forces were mobilized to trace all his contacts, and quarantine
and vaccinate all susceptible individuals. This event followed decades
of work towards eradication by health professionals all over the world.
In 1967 the WHO intensified efforts to eradicate smallpox, and endemic
smallpox was cleared from South America by 1971. In Asia, after efforts
to investigate cases and contain outbreaks were improved, the last case
of smallpox was recorded in 1975. (19) This incredible success was
made possible by a massive amount of political will, an as well as the
successful implementation of technological developments such as the development
of cold chains to bring vaccines safely into remote areas, and the use
of bifurcated needles instead of syinges.
the
last case of small pox, http://www.who.org
Since then significant progress has also been made towards poliomyelitis
eradication. In particular the expansion of the number of countries
with national immunization days in 1996, meant that 2/3 of children under
5 years old had access to oral polio virus immunization. Currently,
the highest priorities for poliomyelitis eradication initiative are implementation
of national immunization days in the remaining endemic countries, and rapid
improvements in surveillance. Expanding the immunization program
into war torn and politically isolated countries, such as the Democratic
Republic of the Congo, Somalia, and Sudan, will be a particular challenge,
and is crucial to final global eradication. (20)
The characteristics of smallpox disease made the possibility of eradication
particularly favorable. The virus has no animal reservoir, in humans
there are no asymptomatic carriers, and it is easy to identify former cases
because of characteristic scarring. (21) Eradication is also theoretically
possible in the case of measles, due to the existence of a effective vaccine,
and no known animal reservoir, and the WHO has announced that measles will
be the next in line to be eradicated after polio. (22) There are characteristics
of measles, though, which may make it much more difficult to eradicate
then either smallpox or polio. These include a particularly high
rate of measles infectivity, which would require at least 90% and possibly
95% of the population to be immune for the incidence to decline towards
zero. Reaching this rate of immunization coverage will be particularly
difficult in developing countries. Lingering questions include the
ability to ensure safe injection practices, the selection of the appropriate
age range to vaccinate in campaigns, and the cost of reaching high enough
coverage for eradication in the poorest countries. (23)
http://www.niaid.nih.gov/publications/pdf/jordan.pdf
http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/su48a12.htm
Vaccine Supply, Safety, Quality, and Delivery
The Childrenís Vaccine Initiative Task force (http://www.vaccines.ch/intro.htm), concerned with global vaccine distribution, has recognized that increased vaccine supply will be necessary to meet disease elimination and eradication goals. The task force is concerned with increasing national self-sufficiency in vaccine supply. Self-sufficiency is the ability of governments to procure enough high quality vaccines to meet the needs of their population through appropriate strategies ìdirected towards more sustainable financing and procurement, local production, and quality-control practicesî. (23)
In 1992 the childrenís vaccine initiative also examined the vaccine quality in 43 vaccine producing countries. The six criteria used to evaluate the vaccines were 1)appropriate legislation 2) clinical review 3) lot release 4) laboratory testing 5) inspections and 6) surveillance. Only 21 countries of the industrialized and developing countries surveyed meet all six criteria. In a survey similar survey of diptheria/pertussis/tetnus vaccine production about 10% of producers failed to meet minimum standards for the purity of toxoids. (23) Large problems were also found in vaccine potency, prompting one researcher to comment that the vaccines were ìso deficient in antigens as to be little more than waterî. (24) This study does emphasize, however, that many vaccine producers in developing countries do produce high quality vaccines.
Many vaccines are perishable and must be kept at a stable temperature while they are transported to the vaccine delivery sight. This requires a network of refigeration and transport called the cold chain. WHO began development of the cold chain in the mid-1970ís to ensure that the major childhood vaccines survive the sometimes two years it may take to deliver the vaccine to the child. New technologies, such as a refrigerator lined with water-filled tubes that can make enough ice in eight hours to store vaccines safely for up to a 16-hour lapse of electricity, have been developed for this purpose. (25) Vaccine vial moniters have been developed so that the oral polio vaccine can be used up to its expiration date. (26)
Increasing Resistance to Antibiotic Drug Therapies
Numerous infectious diseases involve invasion by bacteria pathogens; one treatment to these infections has historically been the use of antibiotic drugs. However, the changing nature of bacterial pathogens and the increasing presence of strains resistant to numerous antibiotic drugs has caused an increased need for vaccine development.
Antibiotics are basically defined as natural substances that inhibit the growth, or proliferation, of bacteria or kill them directly. In practice, most commercially available antibiotics have been chemically altered in the laboratory to improve their potency or to increase the range of species they affect. Antibiotics attack bacteria by entering these microbes and interfering with the production of components needed to form new bacterial cells. This allows the immune system then to be able to combat the remaining bacteria and eliminate them from the system of the host.
Since their discovery, antibiotics have been hailed as ëa miracle drugí because of their extreme effectiveness in combating bacterial infection. However, as antibiotics have become increasingly used, various bacterial strains have also evolved to obtain methods of resisting the effects of certain antibiotics. Bacteria can obtain resistance through various mechanisms. Genetic mutations can create strains resistant to the effects of certain drugs; additionally, bacteria can often acquire resistant genes from other organisms around them. The growing presence of resistant bacterial strains provides an increasingly enormous problem for the treatments of these bacterial infections. (27)
As bacteria can no longer be targeted or killed with certain antibiotics, the need for vaccines to successfully fight infections becomes increasingly apparent. Vaccines that can produce memory B cells for extracellular bacterial infections will allow an individual to fight off the pathogen before systemic infection or disease can occur. This next step is one of the only methods left to combat diseases that have acquired resistance to antibiotic drugs.
Countries of the developing world face the problem of increasing antibiotic resistance in two ways. On the one hand, individuals with bacterial infections in developing countries often have little access to antibiotic drugs because these drugs prove to be scarcely available or prove to be too expensive for purchase and use. Thus, these individuals already infected with the disease will often die for lack of treatment. Additionally, the increasing presence of resistant strains of bacterial pathogens results in the growing spread of infections that have no treatment. The lack of treatment means that these pathogens can grow and spread almost completely unregulated; there is no way to stop these infections.(28)
These factors combined demonstrate the need for vaccine development for bacterial pathogens that exist around the world. Vaccines already available need to be disseminated to world populations for eradication of disease before these strains change again; additionally, vaccines need to be developed for the changed and changing bacteria that exist and continue to escape the immune system of the human body.
For more information on the methods bacteria use to acquire resistance to antibiotic drug treatments and for additional discussion on the growing need for vaccine development for the developing world because of the increasing resistance to antibiotics, please view the following links.
http://www.sciam.com/1998/0398issue/0398levy.html
http://www.who.int/inf-fs/en/fact194.html
http://www.prairiepublic.org/features/healthworks/antibiotics/
Ethics of ClinicalTrials in Developing Countries
Since the number of vaccine trials in all stages of development have increased dramatically in the last decade, concerns have emerged as to the ethics of those trials conducted in developing countries. Often physicians will travel to Third World Nations to test their vaccines for different reasons; volunteers are easier to find or clinical studies abroad will cost less. Additionally, many physicians may travel to areas where infection is endemic to develop their vaccine studies. With the increasing spread of vaccine trials to developing countries, an enourmous amount of literture has surfaced questioning the ethics of these practices.
Objections to trials abroad have targeted the quality of trial that takes place. These critics ask whether "differences in healthcare needs and budgets justify different ethical standards in the developed and developing world."(29) These voices question whether it is ethical to conduct a vaccine trial on a population that may not comprehend all the ramifications of these trials. Additionally, the use of placebo controls have led to much controversy. These critics argue that less intensive and less formulated regimes have gone ahead with their trial research in developing countries where they may not have been able to in nations like the US. Additionally, many of these trials are even funded by foreign governments and the United Nations. (29)
These issues are especially abundant in the study of possible vaccines against the HIV virus. The numerous vaccine trials being conducted for an HIV vaccine has brought ethical issues of patient rights and cultural conflict to the forefront of discussion. On the one hand, researchers often jeopordize their studies by not adequately involving local scientists, doctors, and patients in the developing countries they are conducting their studies in. Without actively informing and involving these local players, scientists from the West re-ignite a form of West verses East conflict; individuals in the developing world increase their hesitation to use vaccines developed by doctors of the West because they are reminded of a history of mistrust in addition to the lack of information and understanding of the methods the vaccine uses to fight infection. This issue can cause barriers to the effective spread of vaccines around the world. Additionally, the lack of involvment of local players often brings into question the medical standards used by the physicians conducting the vaccine trials. Are the involved patients fully aware of the risks they are taking and of the possible consequences of their involvement in each trial? Are the physicians conducting the trials maintaining as sterile and safe an environment that is necessary for medical work of this nature? Will the physician ensure any necessary medical treatment needed in reaction to the vaccine involved or to the diseases present in the individual?(30)
These issues need to be addressed and standards need to be firmly
established and enforced as increasing numbers of vaccine development trials
are initiated in developing countries around the world.