Manufacturing and supply of monovalent oral polio vaccines.

A new polio vaccine was developed, produced and licensed by sanofi pasteur at the request of the World Health Organization (WHO) for mass immunization campaigns in endemic countries such as Egypt. The new vaccine, monovalent oral polio vaccine 1 or mOPV1, is currently used in Egypt as a critical part of a new WHO strategy to end polio type 1 transmission by the end of the year 2005 (types 2 and 3 polioviruses have already been eliminated from Egypt). To answer this specific need, an urgent program was mounted by Sanofi pasteur to manufacture 50million doses for Egypt, in close collaboration with WHO and National Regulatory Agencies (France and Egypt). The joint efforts between manufacturer, regulators and the WHO resulted in the quickest ever vaccine development and licensure and WHO pre-qualification. The production of mOPV was based on existing tOPV but with appropriate "change control" procedures to assure the quality of the product, and to distinguish mOPV from tOPV. Key success factors included clear and careful definition of the project; close collaboration between manufacturer, regulators and WHO; and commitment and motivation of staff. As a result, development and production of mOPV1 vaccine were carried out in a drastically reduced time period, leading to the release and delivery of the first 15 million doses of mOPV1 in April 2005.     

Experimental oral polio vaccines and acquired immune deficiency syndrome

The simian immunodeficiency virus (SIV) of the common chimpanzee is widely acknowledged as the direct ancestor of HIV-1. There is increasing historical evidence that during the late 1950s, kidneys were routinely excised from central African chimpanzees by scientists who were collaborating with the polio vaccine research of Dr Hilary Koprowski, and sent - inter alia - to vaccine-making laboratories in the USA and Africa, and to unspecified destinations in Belgium. While there is no direct evidence that cells from these kidneys were used as a substrate for growing Dr Koprowski's oral polio vaccines, there is a startling coincidence between places in Africa where his CHAT vaccine was fed, and the first appearances in the world of HIV-1 group M and group-M-related AIDS. Because of the enormous implications of the hypothesis that AIDS may be an unintended iatrogenic (physician-caused) disease, it is almost inevitable that this theory will engender heated opposition from many of those in the scientific establishment, and those with vested interests.     

Developments in the production and quality control of poliovirus vaccines -- historical perspectives.

Using virus grown in monkey kidney cells, Salk and his colleagues developed an inactivated poliovirus vaccine (IPV) in 1952. A large-scale field trial showed the vaccine to be safe and highly immunogenic in children, but soon after the vaccine became generally available in 1955, cases of paralytic disease were reported in recipients. Investigations showed that almost all the cases occurred in children who had received vaccine from one particular manufacturer. Extensive studies attributed the disaster to problems with inactivation. Addition of a Seitz filtration step midway during formalin inactivation and extension of the inactivation period resulted in a safe vaccine. No further paralytic cases were observed following the use of several hundred million doses of this improved vaccine. Thus, IPV was safe and caused a dramatic decline in the incidence of poliomyelitis in countries where it was used. A second generation IPV is produced in fermentors using well-characterized cell strains or continuous cell lines. The major breakthrough in the development of live poliovirus vaccine was the application of tissue culture methods for virus attenuation. By 1959 several candidate live oral poliovirus vaccines (OPV) had been developed. These were clinically tested in millions of individuals and found to be safe and effective. Since the attenuated virus strains developed by Koprowski and Cox were more neurotropic in monkeys than the Sabin strains, only the latter was licensed in the USA in 1961 and endorsed shortly after by the World Health Organization (WHO). The widespread use of Sabin's OPV in many countries hastened the development of International Requirements by WHO for OPV in 1962 to define the criteria that ensured the uniformity of batches produced by different manufacturers. These have been updated continuously in light of new information and quality control procedures. Extensive field trials have shown the risk of OPV associated polio to be less than 0.3 per million doses administered.     

Hypotheses and facts

The book, The river, is based on assumptions and not facts. Oral polio vaccine was produced entirely in rhesus monkey kidney cell cultures. Allegations that it was produced in chimpanzee kidneys at the Wistar Institute in Philadelphia or, alternatively, that the vaccine was made in the then Belgian Congo in chimpanzee kidney has no basis in fact. As the only witness to the historical events leading to the development of oral polio vaccine, I have demonstrated in this paper the truthful facts excluding any link between oral polio vaccine and human immunodeficiency virus.     

The control of viral diseases in the developing countries with the use of existing vaccines]

In developing countries, every year about 70 million measles cases occur with 1.5 million deaths, over 200,000 children contract paralytic poliomyelitis, 50 million people get infected with viral B hepatitis causing over 1 million deaths, and several thousand people perish because of yellow fever according to WHO data. At the present time, there are 12 vaccines against viruses: vaccines against German measles and mumps in addition to the above. The universal immunization program (UIP) of WHO targets measles and polio. In 1989, a WHO resolution envisioned a 90% immunization coverage by the year 2000. Measles vaccination is recommended for children aged 9-23 months, since most children have maternal antibodies during the first 3-13 months of age. The Edmonston-Zagreb vaccine provided seroconversion of 92, 96, and 98% for 18 months vs. the 66, 76, and 91% rate of the Schwarz vaccine. In the US, measles incidence increased from 1497 cases in 1983 to 6382 cases in 1988 to over 14,000 cases in 1989, prompting second vaccination in children of school age. The highest incidence of polio was registered in Southeast Asia, although it declined from 1 case/100,000 population in 1975 to .5/100,000 in 1988. Oral poliomyelitis vaccine (OPV) provides protection: there is only 1 case/2.5 million vaccinations. Hepatitis B has infected over 2 billion people. About 300 million are carriers, with a prevalence of 20% in African, Asian, and Pacific region populations. Plasmatic and bioengineered recombinant vaccine type have been used in 30 million people. The first dose is given postnatally, the second at 1-2 months of age, and the 3rd at 1 year of age. Yellow fever vaccine was 50 years old in 1988, yet during 1986-1988 there were 5395 cases with 3172 deaths in Africa and South America. Vaccination provides 90-95% seroconversion, and periodic follow-up vaccinations under UIP could eradicate these infections and their etiologic agents.     

Albert B. Sabin and the Development of Oral Poliovaccine

Abstract. There are many reasons for the modern interest in viral vaccines, but there is no doubt that the key role played by viral vaccines in public health is the major factor since other prophylactic or therapeutic anti-vital products simply do not exist. Viral vaccines have a long history that has been marked by successful events and by tragic accidents. Live viral vaccines are an extraordinary category of biologicals since, despite their reputed efficacy, they were developed by empirical experiments and patient epidemiological observation. From this point of view oral polio vaccine should be considered a 'miracle' since it became a major tool for public health in the 20th century, before we were able to understand the molecular basis of polio virus neurovirulence attenuation. The first evidence that polio virus can be attenuated was provided in the early 1940s by Max Theiler, but it was Hilary Koprowsky who demonstrated further in 1952, that a rodent adapted strain was safe and able to immunise a limited number of volunteers. Koprowsky studies were confirmed later during a mass field trial in Africa. However it is undeniable that the patient and systematic work of Albert B. Sabin was primordial in developing live oral attenuated poliovaccine. The excellence of Sabin's testing of poliovirus neurovirulence in the accurate studies that he developed, enabled him to select, after the cloning of viral populations by plaque assay, the best attenuated variants. It is interesting to remember that the real selective factor that allowed the isolation of attenuated variants was ignored by Sabin and was put forward by Lwoff in the Pasteur Institute, when he described the role of temperature in the selection of cold attenuated mutants. Historically, the first to perform a successful mass vaccination with Sabin oral live poliovaccine were Russian scientists. Oral live poliovaccine was in some cases the origin of paralytic accidents and Sabin strains were involved occasionally in such events. Other attenuated poliovirus strains used in clinical trials as oral vaccine, such as Cox-Lederle type 1 and Usol-D bac type 3, generated in some instances clusters of vaccinees that developed paralysis. An important achievement in the consistency of the Sabin vaccine was the transfer by Albert Sabin to the WHO of the seed material and the responsibility for surveying the quality control and licensing procedure of oral poliovaccine.     

A vision of a world without polio: the OPV cessation strategy.

Once the eradication of wild poliovirus has been confirmed, the public health benefits of routine immunization with OPV will no longer outweigh the burden of disease either due to paralysis caused by OPV (vaccine associated paralytic polio), or by outbreaks caused by circulating vaccine-derived polioviruses. The eventual cessation of OPV use in routine immunization programmes worldwide will become necessary to assure a lasting eradication of polio. As the world moves towards polio eradication and its certification, preparations are therefore being intensified for OPV cessation, and the risk management framework for safe OPV cessation is being put in place. The framework includes bio-containment of all known poliovirus and potentially infected substances, development of an international stockpile of oral polio vaccine, ensuring a mechanism for continued global surveillance and response for polio after eradication has been certified, and national policies if countries decide to continue vaccinating with inactivated polio vaccine (IPV). It is ironic that the vaccine on which the world has depended for polio eradication will itself become a risk to eradication once the transmission of wild poliovirus has been interrupted. Final preparations for the eventual global and simultaneous cessation of OPV will require the same level of international cooperation and coordination that has brought the world to the verge of polio eradication.     

Some ethical issues arising from polio eradication programmes in India

The World Health Organisation's programme for the eradication of poliomyelitis as currently practised in India raises many ethical issues. In this paper we concentrate on just two. The first is the balance to be struck between the risks and benefits generated by the eradication programme itself. The issue of risks and benefits arises in relation to the choice between two different vaccine types available for polio programmes: oral polio vaccine (OPV) and inactivated polio vaccine (IPV). OPV is the vaccine currently used in the eradication campaign in India. We argue that given the current risks/benefits profile of this vaccine, there is an urgent need to review the programme and take remedial action to address existing problems (at least in India). The second issue we discuss is the fact that there is little effort to gain the informed consent of the parents of vaccinated children, as they are not currently told about the potential limitations of OPV or the possibility of vaccine-induced harm. We suggest that such a policy might be justifiable, given the importance of polio eradication, but only if there is a system of compensation for vaccine-induced harm as part of the eradication programme itself. There is a real danger that if these issues are not addressed then public trust in the eradication programme and vaccination programmes as a whole will be lost.     

Family Practitioners' Immunization Consent Practice Washington State, 1986

Of 400 Washington State family practitioners surveyed in 1986, 46% of those who give routine immunizations reported that they require written parental consent before administering vaccine. In all, 57% of respondents said they discuss diphtheria-tetanus-pertussis, measles-mumps-rubella, and oral polio vaccine with their patients. Nearly half provide written information on these immunizations, except for inactivated polio vaccine, for which fewer than 20% of the physicians surveyed provide verbal or written information.     

Control of poliomyelitis by pulse immunisation in Vellore,India.

In a simple study into the control of polio in the Third World a town was divided into 16 zones and pulses or oral polio vaccine given at one station in each zone, after extensive publicity about the campaign. Some 62% of children received three doses of the vaccine and the incidence of polio fell dramatically over the study period. It is suggested that this method is applicable to similar communities because it is cheap, effective, and able to be extended to unimmunised communities when resources allow.     

The Sabin live poliovirus vaccination trials in the USSR, 1959.

Widespread use of the Sabin live attenuated poliovirus vaccine has had tremendous impact on the disease worldwide, virtually eliminating it from a number of countries, including the United States. Early proof of its safety and effectiveness was presented in 1959 by Russian investigators, who had staged massive trials in the USSR, involving millions of children. Their positive results were at first viewed in the United States and elsewhere with some skepticism, but the World Health Organization favored proceeding with large-scale trials, and responded to the claims made by Russian scientists by sending a representative to the USSR to review in detail the design and execution of the vaccine programs and the reliability of their results. The report that followed was a positive endorsement of the findings and contributed to the acceptance of the Sabin vaccine in the United States, where it has been the polio vaccine of choice since the mid-1960s.     

Polio vaccine: the first 50 years and beyond. Summary of the meeting and next steps.

A conference on "Polio vaccine: the first 50 years and beyond" was held in Toronto, Canada, June 2005. The purpose of the conference was to bring together regulators, manufacturers, academics and public health authorities to celebrate the accomplishments of the past 50 years, to consider the challenges of achieving and sustaining polio eradication and to review standardization and regulatory issues around existing and new polio vaccines. In the final session of the conference the following summary of the meeting was presented.     

Excretion of wild-type and vaccine-derived poliovirus in the feces of poliovirus receptor-transgenic mice

The emergence of circulating vaccine-derived poliovirus (cVDPV) strains in suboptimally vaccinated populations is a serious threat to the global poliovirus eradication. The genetic determinants for the transmissibility phenotype of polioviruses, and in particularly of cVDPV strains, are currently unknown. Here we describe the fecal excretion of wild-type poliovirus, oral polio vaccine, and cVDPV (Hispaniola) strains after intraperitoneal injection in poliovirus receptor-transgenic mice. Both the pattern and the level of fecal excretion of the cVDPV strains resemble those of wild-type poliovirus type 1. In contrast, very little poliovirus was present in the feces after oral polio vaccine administration. This mouse model will be helpful in elucidating the genetic determinants for the high fecal-oral transmission phenotype of cVDPV strains.     

Characterization of CHAT and Cox type 1 live-attenuated poliovirus vaccine strains

CHAT and Cox type 1 live-attenuated poliovirus strains were developed in the 1950s to be used as vaccines for humans. This paper describes their characterization with respect to virulence, sensitivity for growth at high temperatures, and complete nucleotide and amino acid sequences. The results are compared to those for their common parental wild virus, the Mahoney strain, and to those for two other poliovirus strains derived from Mahoney, the Sabin 1 vaccine strain and the mouse-adapted LS-a virus. Analysis of four isolates from cases of vaccine-associated paralytic poliomyelitis related to the CHAT vaccine revealed genetic and phenotypic properties of the CHAT strain following replication in the human gut. CHAT-VAPP strain 134 contained a genome highly evolved from that of CHAT (1.1% nucleotide differences), suggesting long-term circulation of a vaccine-derived strain in the human population. The molecular mechanisms of attenuation and evolution of poliovirus in humans are discussed in the context of the global polio eradication initiative.     

Oral vaccines: new needs, new possibilities

Vaccination is an important tool for handling healthcare programs both in developed and developing countries. The current global scenario calls for a more-efficacious, acceptable, cost-effective and reliable method of immunization for many fatal diseases. It is hoped that the adoption of oral vaccines will help to provide an effective vaccination strategy, especially in developing countries. Mucosal immunity generated by oral vaccines can serve as a strong first line of defense against most of the pathogens infecting through the mucosal lining. Advances in elucidating the mechanism of action of oral vaccines will facilitate the design of more effective, new generation vaccines. There are promising developments in the use of different agents to effectively deliver the vaccine candidate. It is hoped that ongoing research may be able to set another cardinal point, after polio vaccine, in eradicating infectious diseases.     

Epidemiology and the emergence of human immunodeficiency virus and acquired immune deficiency syndrome

Although acquired immune deficiency syndrome (AIDS) was first described in the USA in 1981, there is evidence that individual cases occurred considerably earlier in Central Africa, and serological and virological data show human immunodeficiency virus (HIV) was present in the Democratic Republic of Congo (DRC) as far back as 1959. It is likely that HIV-1 infection in humans was established from cross-species transmission of simian immunodeficiency virus of chimpanzees, but the circumstances surrounding this zoonotic transfer are uncertain. This presentation will review how causality is established in epidemiology, and review the evidence (a putative ecological association) surrounding the hypothesis that early HIV-1 infections were associated with trials of oral polio vaccine (OPV) in the DRC. From an epidemiological standpoint, the OPV hypothesis is not supported by data and the ecological association proposed between OPV use and early HIV/AIDS cases is unconvincing. It is likely that Africa will continue to dominate global HIV and AIDS epidemiology in the near to medium-term future, and that the epidemic will evolve over many decades unless a preventive vaccine becomes widely available.     

The Jezierski papers: live polio vaccine development in colobus monkey cells but not chimpanzee cells in the Belgian Congo, 1952-1958

A reading of ten relevant papers by Alexandre Jezierski provides evidence for the only attempt in Central Africa to develop a live oral polio vaccine (OPV) from growing reference wild polio strains to 210 passages in colobus monkey tissue culture, and experimental administration to about 25 humans. Chimpanzees were used as a human model, but their tissues or kidneys were absent from the passage and production line of the proposed vaccine. Thus, the implication published by Hooper that Jezierski had produced a candidate OPV that might have contained chimpanzee viruses, possibly simian immunodeficiency virus cpz or the precursor of human immunodeficiency virus-1 group M, is incorrect.     

Responsibility for truth in research

For over half a century, cell cultures derived from animals and humans have served researchers in various fields. To this day, cross-contamination of cultures has plagued many researchers, often leading to mistaken results, retractions of results, cover-ups and some out-and-out falsification of data and results following inadvertent use of the wrong cells. Also, during years of examining cultures for purity we learned that many virologists were not too concerned about the specificity of the cultures they used to propagate the particular virus under study as long as the substrate (whatever it might have been) gave optimal virus yield. Polio virus propagates in primate cells, and much research has involved cells from man and various species of primates. In the 1950s a large number of chimpanzees were held in captivity in Africa for extensive studies of the efficacy of polio vaccine in production at the Wistar Institute in Philadelphia and elsewhere. Chimpanzee tissues, particularly kidneys, were thus readily available and could have also provided substrates for polio virus production, since little was known about the purity of substrates and little attention was paid to their specificity at that time.     

Twenty-Eight Years of Poliovirus Replication in an Immunodeficient Individual: Impact on the Global Polio Eradication Initiative

There are currently huge efforts by the World Health Organization and partners to complete global polio eradication. With the significant decline in poliomyelitis cases due to wild poliovirus in recent years, rare cases related to the use of live-attenuated oral polio vaccine assume greater importance. Poliovirus strains in the oral vaccine are known to quickly revert to neurovirulent phenotype following replication in humans after immunisation. These strains can transmit from person to person leading to poliomyelitis outbreaks and can replicate for long periods of time in immunodeficient individuals leading to paralysis or chronic infection, with currently no effective treatment to stop excretion from these patients. Here, we describe an individual who has been excreting type 2 vaccine-derived poliovirus for twenty eight years as estimated by the molecular clock established with VP1 capsid gene nucleotide sequences of serial isolates. This represents by far the longest period of excretion described from such a patient who is the only identified individual known to be excreting highly evolved vaccine-derived poliovirus at present. Using a range of in vivo and in vitro assays we show that the viruses are very virulent, antigenically drifted and excreted at high titre suggesting that such chronic excreters pose an obvious risk to the eradication programme. Our results in virus neutralization assays with human sera and immunisation-challenge experiments using transgenic mice expressing the human poliovirus receptor indicate that while maintaining high immunisation coverage will likely confer protection against paralytic disease caused by these viruses, significant changes in immunisation strategies might be required to effectively stop their occurrence and potential widespread transmission. Eventually, new stable live-attenuated polio vaccines with no risk of reversion might be required to respond to any poliovirus isolation in the post-eradication era.