Finish Polio: Evolutionary Medicine Principles and the Eradication of Polio
Final Project for BIO 540 – Evolutionary Medicine
Margaret Guerrera
BIO. 540
December 12, 2007
Discussion of the Issues
Introduction
As of November 27, 2007 there were 763 reported cases of polio world-wide. 676 of which occurred in endemic countries and 87 of which occurred in non-endemic countries. (www. polioeradication.org ) This is a far cry from the 350,000 cases of polio that occurred per year prior to 1988 which is the year the Global Polio Eradication Initiative (GPEI) came into existence (Aylward, 2006). Since its inception, the GPEI has evolved into one of the largest international health efforts in the history of public health and has operated to eradicate polio in every country in the world and from 1988 until today, this initiative has decreased polio cases by 99% (Aylward, 2006). The initial goal of the effort was global eradication of polio by the year 2000, however, the goal was not reached but one can see that considerable progress has been made. Today, polio has been eradicated in North and South America, the Western Pacific and all but four countries of Africa and Asia (World Health Organization/GPEI, Annual Report, 2006). According to the GPEI 2006 Annual Report, “Country after country disappeared from the “polio map” and an estimated five million people who would otherwise be paralyzed are walking today” (World Health Organization/GPEI, Annual report, 2006). See Figure 1.
Figure 1. Comparison of countries with active poliovirus transmission in 1988 and at the end of January 2006. In 1988 there were over 125 endemic countries whereas in 2006 there were only four endemic countries and eight that had been polio-free but had become re-infected (Alyward, 2006).
As of today, four countries continue to be endemic for polio. They are Afghanistan, India, Nigeria and Pakistan. These countries have, up until recently, never made any real effort to stop indigenous polio. Other countries have reported cases of polio as a result of importation of the virus (http://www.cdc.gov/).
In 2003, the eradication effort was threatened when political leaders in Nigeria decided to halt the vaccination effort in their country amid rumors regarding the safety of the vaccine. As a result of the prolonged suspension, 18 previously polio-free countries became infected by polioviruses originating in northern Nigeria (Aylward, 2006). It has been estimated that, between 2003 and 2006, the suspension resulted in 1500 children suffering unnecessarily from acute flaccid paralysis (AFP) (Zaracostas, 2006).
Eradication of polio appears to be within reach however, the effort can very easily be set back as demonstrated by the circumstances in Nigeria and other endemic countries. Figure 2 demonstrates how readily importation occurs from endemic countries to non-endemic countries.
Figure 2: Countries Reporting Cases of Wild Poliovirus Infection in 2006 and Routes of Viral Spread from Countries with Endemic Disease from 2002 to 2006.
Data for cases in 2006 are from the World Health Organization. Arrows indicate some of the international importation events during this period, as determined by means of poliovirus surveillance and genetic analysis. Shading denotes countries with reported cases of polio in 2006; red represents the four countries where polio is still endemic and orange represents countries with cases or outbreaks after importation. (Pallansch, 2006)
The process of eradication moved stealthily along for over 14 years at a cost of 5.3billion dollars (NIAID presentation, 2007). See Figure 3. While 763 cases seem like so few, the challenge for eradication of polio has just begun. As Paul Ewald, an expert in Evolutionary Medicine, stated in his book Plague Time:
“The completion of the campaigns often requires that the last holdouts are persuaded to cooperate or forced to submit. All eradication campaigns suffer from this Achilles’ heel. Some people want their houses fumigated, others resist. Some prefer to have their contagious illness treated, other refuse. If we are to win some of the more winnable wars- those against measles and polio, for example- we may need to violate more rules than we have to date”(Ewald, 2002).
This passage, to some degree, describes the current situation of polio eradication. The investment of time, money, and human energy has been immense. With all of this at stake, it appears that there is no going back and that eradication is the only option. Without it, polio could re-emerge as a global pandemic.
Figure 3: Major sources of the external financing required for the global polio irradication initiative between 1988 and 2008(Alyward, 2006).
How and when will the story of polio eradication end? At this stage of the game, there are many factors to be considered. Through the next several pages of this report, I hope to educate the reader on polio, polioviruses, vaccines and the challenges and barriers that lay ahead. Moreover, I hope to shed light on the role evolutionary biology has played in the process of eradication and, at the same time, propose a plan that utilizes evolutionary principles, to help in the final eradication effort.
Overview of the Disease: People still get polio? Who Knew?
If you did not know people still get polio, you are not alone. Polio has been eradicated in the US. The last known transmission of wild virus occurred in 1979 and it was found that the virus that caused this outbreak was imported from the Netherlands and it affected a small number of unvaccinated individuals (www.cdc.gov). In 1994, the WHO certified the Western Hemisphere free of indigenous wild poliovirus and that one type of polio virus (P2) has been eradicated (http://www.cdc.gov/). Unless you are paying close attention to global public health issues, are a member of Rotary International* or are a student of evolutionary medicine, the odds are that you thought polio was gone forever. Unfortunately, it is not gone. As mentioned early, polio still exists endemically in several countries and while there are less than 1000 cases in the world presently, it has the potential ,if left unchecked, to become a serious health threat once again.
Sporadic cases continue to occur throughout the world but in highly immune areas these small outbreaks burn themselves out quickly and do not become epidemic (Bull, 2001). From where do these sporadic cases originate? Thanks to evolutionary biologists, the answer can be found through phylogenetic analysis of the offending virus. Phylogenetics is the study of evolutionary genealogies and is now a standard part of any disease epidemiology; it utilizes a branching tree that represents the evolutionary history of the lineages being studied and it has become indispensible in identifying disease reservoirs and in tracking step-by-step transmission of some viruses of which polioviruses are included (Bull, 2001). In most cases, the biologists have been able to trace the roots of these sporadic outbreaks to an imported wild type or a vaccine derived virus (Bull, 2001).
*Rotary International has played a pivotal role in the eradication effort contributing more than $600 million dollars and countless volunteers to the effort. (Aylward, 2006)
What exactly is Polio?
Polio is caused by the smallest viruses that infect humans called enteroviruses that belong to the Picornaviridae family (Kew, 2005). Humans are the only known reservoir. There are three serotypes: P1, P2 and P3 and immunity from one does not confer immunity to the others (http://www.cdc.gov/). Between strains within each type there are differences that can be delineated by the sequence of the individual components in the viral genome which helps to identify it as imported, endemic wild type or vaccine-derived virus (Kew, 2005). Polioviruses attach to and enter cells via a specific receptor on the cytoplasmic membrane. The receptor is called CD 155 which is a cell to cell adhesion molecule that is found only on the cells of humans, higher primates and Old World monkeys (Kew, 2005). The viruses have a high evolutionary rate which yields a major advantage: it permits, during natural replication, the patterns of polio transmission to be followed with unparalleled precision (Kew, 2005). Polioviruses are stable viruses even in an acid environment and are able to survive for long periods of time in water and sewage (Melnick, 1989).
Polio is a highly contagious disease. In endemic areas, many children are infected within the first year of life. The largest percentage of infections does not cause any symptoms or may cause only a mild illness. However, in about 1% of cases, Acute Flaccid Paralysis (AFP) occurs which can lead to lifelong paralysis and lameness. (www.cdc.gov) Transmission peaks in the summer and fall and decreases during winter hence it exhibits seasonality, however, these seasonal differences are less pronounced in tropical areas (www.cdc.gov). It is transmitted via the fecal-oral route and the oral-oral route. Major risk factors for transmission include the following (Kew, 2005):
1. Poor sanitation and hygiene
2. Tropical and subtropical conditions
3. Large birth cohorts
4. High population densities
5. The number and density of non-immune persons
Further consideration, in terms of emergence and spread, is that the prior elimination of indigenous wild polio virus circulation increases the risk because non -immune susceptible individuals accumulate rapidly in the absence of high rates of polio vaccine coverage and naturally acquired immunity (Kew, 2005).
According to the Center for Disease Control:
“The virus enters through the mouth, and primary multiplication of the virus occurs at the site of implantation in the pharynx and gastrointestinal tract. The virus is usually present in the throat and in the stool before the onset of illness. One week after the onset there is fewer viruses in the throat, but virus continues to be excreted in the stool for several weeks. The virus invades local lymphoid tissue, enters the bloodstream, and then may infect cells of the central nervous system. Replication of poliovirus in motor neurons of the anterior horn and brain stem results in cell destruction and causes the typical manifestations of poliomyelitis. Many persons who develop AFP recover completely and in most, muscle function returns to some degree however, weakness or paralysis still present 12 months after the acute onset is usually permanent” (http://www.cdc.gov/).
The Vaccines
Currently, there are two vaccines available: the inactivated poliovirus vaccine or IPV and the oral polio vaccine or OPV. IPV is also known as the Salk vaccine- named for the man who developed the vaccine in the 1950s. IPV is made from inactivated or killed polioviruses (all three types are used) and requires that it be given by injection (http://www.cdc.gov/).
OPV, also known as the Sabin vaccine- named for the man who developed the vaccine, contains live viruses that have been attenuated so that they are no longer neurovirulent for humans. In its trivalent form, it contains all three types of polioviruses. OPV induces not only serum antibodies but also local, secretory antibodies in the intestines of immunized individuals which allows not only for the protection of the individual but also serves as a barrier to the circulation of wild viruses in the general population (Melnick, 1989) – an excellent illustration of practically applied evolutionary principles. The live attenuated viruses are shed in the feces of the immunized individual and consequently provide passive immunity to additional members of the community. This is referred to as “herd immunity” (Paul, 2005).
OPV is used in developing countries and has several advantages over IPV which include (Kew, 2005):
1. Ease of administration
2. Suitability for mass vaccination campaigns
3. Induction of intestine mucosal immunity which provides protection for the individual and the community(herd immunity)
4. Low cost
In the developed world, things are a bit different. For example, IPV has been used exclusively since 2000 to immunize children in the US (www.cdc.gov). IPV protects only the vaccinated individual. The virus does not replicate in the intestine and therefore does not shed in the fecal material. In this case, if enough members of a community are vaccinated “herd protection” not immunity occurs (Paul, 2005). It is the vaccine of choice in the US because polio transmission has been eliminated and OPV has the capability of causing Vaccine Associated Paralytic Polio (VAPP) in non-immune household contacts. VAPP is an important issue that will be discussed in the next section.
Challenges to the Eradication Effort
The primary challenges to the eradication of polio center around the vaccination program. As described previously, the vaccines themselves are not without weaknesses. The global campaign has suffered setbacks related to the vaccines and the vaccination programs and of course financial support particularly in poor countries will remain a major obstacle even after the WHO certifies the world finally free of polio.
The Vaccines – How can vaccines that work be part of the problem?
Social and Cultural Issues:
How can it be that these vaccines that have been used for over 50 years are part of the problem?
There are several issues that need to be considered. The first one is related to public distrust of the vaccine. As previously mentioned, the most recent threat began in 2003 in the state of Kano in Northern Nigeria. A small number of local opinion leaders began questioning the basis for the mass polio immunization campaigns. A wide range of theories were suggested regarding the safety of OPV including that it contained HIV and anti-fertility agents. Their fears were not completely unfounded. Since at least the mid to late 1990s until very recently, it had been theorized that HIV, the virus that causes AIDS, may have crossed into humans as a result of contamination of the OPV. The claim was that a simian immunodeficiency virus (SIV) was transmitted to humans when chimpanzee tissues were allegedly used in the preparation of OPV (Hooper, 1999 as cited in Worobey, 2004). Using evolutionary methods, specifically phylogenetic analysis, it was determined that the SIV was genetically distinct from all strains of HIV-1 which provided direct evidence that the chimpanzees were not the source of the AIDS pandemic (Worobey, 2004).
The fear and distrust of the vaccine delivered a major blow to the campaign and by the end of August 2003 political leaders in Kano and adjoining states had decided to suspend the polio campaign until the rumors could be addressed. This single decision caused over 1000 children to become infected with poliovirus and subsequently develop paralysis. (Alyward, 2005)
Factors that contributed to the situation in Nigeria have been studied. The situation in 2003 was a direct result of local communities concern over the vaccine but more importantly their distrust of the two primary organizations involved in the vaccine program – the World Health Organization (WHO) and UNICEF both of which were perceived as “Western and Judeo-Christian” by the Muslims of Kano (Obadare, 2005). Moreover, there was an overall pre-existing distrust of their own government that dated back to Africa’s colonial past that was not understood by these organizations and was not taken into consideration when the GPEI made a major push to get every child in Africa immunized completely in early 2003 (Obadare, 2005). According to Obadare:
“The coincidence of this flawed approach with a perspective that regards western biomedicine as being inherently sufficient cannot be overemphasized. Nor can it be easily dismissed that the approach itself seems to recall the old colonist attitude towards “preternaturally diseased African subjects” (Obadare, 2005).
Others have suggested similar issues of distrust and have additionally suggested that the health care structure contributed to the problem. As an example, many individuals in the community did not understand why polio was so important when, more times than not, their basic health care needs were not addressed (Yahya, 2007). In many instances, children were being vaccinated by children. It has been reported that many of the vaccinators are young girls between the ages of 9 and 14 years old(Yahya, 2005). In addition, children were receiving more than the recommended number of doses, sometimes up to 10 when the recommended number is four and no information was given to or shared with parents regarding the vaccine process or the potential risks associated with the vaccine (Yahya, 2005).
In a somewhat similar situation, polio incidence had increased in India. The year 2006 saw an increase in polio cases from 66 in the previous year to 597(Bagchi, 2007). Some have suggested that a large part of problem was related to the ethical practices of the WHO. Issues of informed consent and non-disclosure of the risks specifically that of VAPP, were at the center of this debate (Paul, 2005).
The experience in Nigeria lead to a change and has opened important lines of communication at the global and national levels which fostered a deeper understanding and sensitivity that was needed to move the program forward (Yahya, 2005). The success of the eradication effort now depends in part on direct oversight by all political, traditional, religious, and community leaders in each area in which the disease is endemic to ensure that every child is vaccinated (Aylward, 2005).
Vaccine Associated Paralytic Polio (VAPP):
It is possible that the element of distrust is not necessarily without warrant. Students of evolutionary medicine could easily appreciate what could happen when individuals are immunized with live attenuated viruses that are capable of replication. As described earlier, after ingestion, OPV replicates in the human intestines. Just like wild type polioviruses, the VDPV has a high evolutionary rate which results in the generation of many mutants some of which may exhibit phenotypes of neurovirulence much like that of wild-type polio viruses. A high proportion, perhaps 30% or more, excrete these strains, referred to as Vaccine Derived Polio Viruses (VDPV). VDPVs can spread readily to non-immune subjects who come in contact with primary vaccinated individuals (Nathanson, 2002).
At a population level, these characteristic have important implications. If close to 100% of the population is immunized, the vaccinated individuals exposed to the attenuated vaccine virus develop immunity before the revertant strains develop and can cause paralysis. However, if immunization coverage is incomplete and a large proportion of the population does not participate, then a VDPV may spread sequentially through several non-immunized persons accumulating mutations and reversions, which will increase the likelihood that some individuals will develop paralytic poliomyelitis. To put it simply, a vaccine program has the potential to inadvertently initiate an outbreak of polio similar to natural outbreaks. (Nathanson, 2003).
Several examples of this have been documented. In Nigeria, 93 children were paralyzed by type 2 polio (Mac Kenzie, 2007) Remember, wild Type 2 poliovirus has been eradicated world-wide. How then did these children become infected? The OPV is a trivalent vaccine which means it contains all three serotypes including P2. The cause of their paralysis was due to VDPV. From an evolutionary perspective, one might ask, “If P2 has been globally eradicated, why is it still in the vaccine? “.
In Hispaniola in 2000, 21 case of AFP were reported and laboratory analysis confirmed the presence of circulating VDPV type 1 in stool samples obtained from these individuals (Vinje, 2004). Further investigation revealed that VDPV was found circulating in sewage, streams, canals and public restrooms. Remember, all polio had been eradicated in the western hemisphere since 1994. Again, one must be compelled to ask “How is this possible?” A phylogenetic analysis conducted by the authors, determined that these viruses were highly related to circulating VDPV isolated from clinical cases and formed distinct subclusters related to geographic area.
In addition to Hispanola and Nigeria, there have been other outbreaks caused by VDPVs between the years 2000 and 2005 and these include outbreaks in the Phillipines, Madagascar, China and Indonesia (Aylward, 2006).
It has been suggested that any country using OPV that has populations in which vaccine coverage is insufficient should be alert to the risk of emergence of VDPVs (Dowdle, 2006). Based on these examples, it would also make sense to remove P2 from the OPV. This would minimize the amount of polio cases caused by VDPVs.
Monovalent vaccines, generated from a single strain of virus, are currently being used in an effort to reduce VDVPs (Aylward, 2006). The problem with this is that it only protects against a single type. As mentioned early, immunity against one serotype does not provide immunity against the other types. Wild Type 1 and 3 continue circulate. It would seem that a better vaccine might be a bivalent containing both P1 and P3 viruses or a vaccine that focuses on the genetic similarities of all three polioviruses and can provide protection against all three serotypes. Additionally, it would make sense to investigate what makes some infections with polioviruses benign and others so virulent. In other words, why are 99% of infections not problematic to the host and the remaining 1% so devastating? Perhaps further investigation in this area would yield a better vaccine.
VDVP raises further issues. Once global eradication has been certified, the use of OPV must be stopped (Heymann, 2006). In the immediate post-eradication period, it will be important to protect against the reintroduction of wild type polioviruses and the continued circulation of VDPV. The use of IPV is a possible solution and appears to have worked well in the US. However, the vaccine is not as accessible to those countries with limited financial resources and public health infrastructure (Nathanson, 2002). Research is necessary to develop either a better oral vaccine with minimal or no possibility of viral shedding in feces or a less expensive and easy to use IPV. In addition, if the current IPV becomes the solution, a plan for the administration of the vaccine will need to be developed given that it will have to be injected and that is does not provide herd immunity. As suggested above, perhaps it is time to move away from the traditional OPV and IVP and look at things from a different perspective- perhaps from an evolutionary perspective.
Call for Action:
The world is on the verge of eradicating this disease. It will be only the second disease in history that has been eradicated. As it stands presently, there is so much at stake that there is no turning back and that the only acceptable end point is eradication. To drop the ball at this point could result in dire consequences. Polio is highly contagious and can move quickly throughout communities, countries and ultimately the world. To simply control transmission through the use of the present vaccine cannot be sustained. I am proposing the following muti-pronged approach. The 5 million dollar budget I have been allocated will not come close to covering all that I propose but it will be helpful. I will address the budget following my plan of action.
Evolutionary Principles Can Help WHO?- Key Points of the Plan
I propose the following:
1. That the WHO and other organizations work with with local leaders in the remaining endemic countries to better understand and learn the social and cultural barriers that prevent the eradication of polio in their countries. Educating people is not enough. Paternalism on the part of the organizations is not appreciated in these countries. By recruiting knowledgable individuals,knowledgable in the cultural, social and religious practices of the peopleas well as in the eradication effort,it will be easier to work with local community leaders in an effort to move the initiative forward; instead of what seems to be happening- one step forward and two steps back so to speak.
2. Improving the health care infrastructure. With the amount of money that has been poured into this effort over nearly 20 years, it appears that perhaps a better investiment would have been to build well staffed clinics in local communities that could not only address polio vaccination but other vaccinations and other basic health care needs.
3. A Better Vaccine – Research for a better vaccine is important. It may not seem important at this late stage of the effort but it is crucial to the success of the GPEI. The vaccines for the most part are the same vaccines used since 1955. While they have been instrumental in bringing the effort to its current state, they will not aid in sustaining the elimination of the viruses and perhaps be responsible for reintroduction. Currently, IPV is too expensive for these remaining countries to purchase and it is more difficult to administer. The word is out (Heyman, 2005 and Griffiths, 2006) but the money needs to get out to researchers. Without this critical change the entire eradication effort may be in jeopardy.
In my limited investigation, I was not able to find any publized research or grant opportunities related to new or improved polio vaccines therefore I propose the following plan of action.
Plan of Action:
As was stated earlier,$ 5 million dollars compared to the $5.3 billion dollars spent thus far is a drop in the bucket, however it can be put to good use to aid in the effort of erradication in these final four countries with the added benefit of sustaining erradication on a world-wide scale. Therefore I propose that the $5 million be used to fund up to 3 research grants at $1.63 million dollars each to be used for the sole purpose of funding research for new polio vaccinations that eliminate the problems associated with the current vaccines. Since time is of the essence the grants will be offered to individuals/institutions already experienced in the process of vaccine research and development. The money will be available over a three year period and can be pulled for a lack of progress. The money can be used for, among other things, appropriate laboratory equipment, salary support for the research team, and travel related to the research. Preference will be given to those instituitions who contribute monetary and “in kind” support toward the research effort equal to 30-50% of the total grant amount. Research progress and financial status will be evaluated on an annual basis by an independent research team and financial auditor, respectively.
What to do with $5 million? – The Recommended Budget:
I determined the grant amount based on the following costs:
Suggested Research Team Salary Expenses(http://www.bls.gov/ ):
1. Lead Research Scientist (MD or PhD) - $465,000
2. Epidemiologist or Biology Scientist - $211,050
3. Operation Research Analyst (20 hours per week) – $103,614
4. Biotechnicians or Graduate Student Researchers (3) – $114,691
5. Administrative Assistant – $124,800
Subtotal = $1,019,155
Non-Salary Expenses (My own estimates based on my budget development experience):
1. Capital Equipment - $450,000
2. Travel and associated costs – $9,000
3. Non Capital Equipment and Supply Costs - $150,000
Subtotal = $609,000
Total = $1,628,155 per grant
The 30-50% monetary and “in kind” support from the grantee institution would cover the benefits for the research team which is estimated to be approximately 35% of the salary costs and overhead expenses such as the research laboratory space and utilities(lights, HVAC).
Progress will be monitored by the grantees’ submission of quarterly reports which describes the research goals and progress toward those goals. Financial statements including budgetary expenditures will be included in these reports. Financial audits will be conducted annually. Furthermore, site visits will be conducted annually by a team of independent researchers to assess the teams progress toward achieving the goals set. The expenses for the audits and site visits will be supported by the remaining $200, 000.
References Cited
Alyward, R.B., and D. Heymann (2005). “Can we Capitalize on the Virtues of Vaccines? Insights from the Polio Eradication Initiative”. American Journal of Public Health. 95(4); 773-777.
Alyward R.B., (2006). “Eradicating Polio: Today’s Challenges and Tomorrow’s Legacy”. Annals of Tropical Medicine and Parasitology. 100 (5 and 6); 401-413.
Bagachi, S., “Polio Eradication Setback in India”(2007), CMAJ ; p176.
Bull, J. and H. Wichman (2001) “Applied Evolution”. Annual review of Ecology and Systematics. 32; 183-217.
Dowdle, W., and O. Kew (2006). “Vaccine-Derived Polioviruses: It is time to stop using the word rare?” The Journal of Infectious Diseases. 194; 539-541.
Ewald, P. (2002). Plague Time. First Anchor Books. New York.
Global Polio Eradication Initiative: Annual Report (2006). Retrieved from http://www.polioeradication.org/ on November 3, 2007.
Griffiths, E. Wood, D and L. Barreto (2006). “Polio Vaccine: The First Fifty Years and Beyond”. Biologicals; 34; 73-74.
Heymann, D., Sutter, R., and R.B. Aylward (2005). “A Global Call for New Polio Vaccines. Nature. 434: 699-700.
Heymann, D., Sutter, R., and R.B. Aylward (2006). “A Vision of a World without Polio; the OPV Cessation Strategy”. Biologicals 34; 75-79.
Hooper, E. (1999). The River: A Journey Back to the Source of HIV and AIDS as cited in Worobey, M. (2004).
Kew, O, Sutter, R., de Gourville, E., Dowdle, W., and M. Pallansch (2005). “Vaccine-Derived Polioviruses and the Endgame: Strategy for Global Polio Eradication”. The Annual Review of Microbiology 59: 587-635.
MacKenzi, D., (2007). “Live Vaccine Leaves Door Ajar to Polio”. New Scientist; 195.2624; p.12.
Melnick, J. (1989). “The Polio Virus and the Vaccines”. World Health. Retrieved from Academic OneFile. Gale. November 20, 2007.
Nathanson, N., and P. Fine (2002). “Poliomyelitis Eradication: A Dangerous Endgame”. Science, 296; 269-270.
National Institute of Allergy and Infectious Diseases (2007). Proceedings from “Polio Immunization: Moving Forward Conference: September 19, 2007. Retrieved from http://www.niaid.nih.gov/ on November 23, 2007.
Obadare, E. (2005). “A Crisis of Trust: history, politics, religion and the polio controversy in Northern Nigeria”. Patterns of Prejudice 39 (3), 265-284.
Pallansch, M. and S. Hardeep (2006). “The Eradication of Polio-Progress and Challenges”. New England Journal of Medicine. 355 (24); 2508-2511.
Paul, Y., and A. Dawson (2005). “Some Ethical Issues Arising from Polio Eradication Programmes in India”. Bioethics 19(4); 393-406.
Vinje, J., Gregoricus, N., Martin, J., Gary Jr., H., Caceres, V., Venezel, L., Macadam, A., Dobbins, J., Burns, C., Wait,D., Ko, G., Landaverde, M., Kew, O and M. Sobsey (2004). “Isolation and Characterization of Circulating Type 1 Vaccine-Derived Poliovirus from Sewage and Stream Waters in Hispaniola”. The Journal of Infectious Diseases. 189; 1168-1175.
Worobey, M., Santiago, M., Keele, B., Ndjango, J., Joy, J., Lambama, B., Dhed, B., Rambaut, A., Sharp, P., Shaw, G., and B. Hahn (2004). “Contaminated Polio Vaccine Theory Refuted”. Nature. 428; 820.
Zaracostas, J. (2006). “Failed Vaccine Campaigns May Lead to Polio Resurgence, experts warn”. British Medical Journal 333; 823.
Web Sites Used:
Center for Disease. http://www.cdc.gov/ . Poliomyelitis. Retrieved November 3, 2007.
United States Department of Labor: Bureau of Labor Statistics. http://www.bls.gov/ Salary Information. Retrieved December 6, 2007.
Global Polio Eradication Initiative. http://www.polioeradication.org/ . Weekly Count of Reported Polio Cases. Retrieved November 30, 2007.