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.     

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.     

Untruths and consequences: the false hypothesis linking CHAT type 1 polio vaccination to the origin of human immunodeficiency virus

A book published in 1999 hypothesized that the scientists who worked with the CHAT type 1 attenuated polio strain tested in the former Belgian Congo in the late 1950s had covertly prepared the vaccine in chimpanzee kidney cells contaminated with a simian immunodeficiency virus, which evolved into HIV-1 group M. This paper summarizes the results of the investigation conducted by the author to determine the legitimacy of the accusation. Testimony by eyewitnesses, documents of the time, epidemiological analysis, and ancillary phylogenetic, virologic and PCR data all concur to reject the hypothesis as false and without factual foundation.     

First decade (1950-1960) of studies and trials with the polio vaccine.

The chronology of the development of polio vaccines following the first human trials of attenuated poliovirus vaccine in 1950 is described by me as a witness to the first decade of trials and tribulations following my discovery of polio vaccine in 1950. Mass vaccination trials are considered to be the most important phase of the discovery of oral polio vaccine (OPV). These took place in the Belgian Congo, Poland, Croatia, Switzerland, and finally in the former Soviet Union. By 1960, approximately 13 million individuals had been vaccinated with the Koprowski oral polio vaccine and over 11 million with the Sabin vaccine.     

Next Generation Inactivated Polio Vaccine Manufacturing to Support Post Polio-Eradication Biosafety Goals

Worldwide efforts to eradicate polio caused a tipping point in polio vaccination strategies. A switch from the oral polio vaccine, which can cause circulating and virulent vaccine derived polioviruses, to inactivated polio vaccines (IPV) is scheduled. Moreover, a manufacturing process, using attenuated virus strains instead of wild-type polioviruses, is demanded to enhance worldwide production of IPV, especially in low- and middle income countries. Therefore, development of an IPV from attenuated (Sabin) poliovirus strains (sIPV) was pursued. Starting from the current IPV production process based on wild type Salk strains, adaptations, such as lower virus cultivation temperature, were implemented. sIPV was produced at industrial scale followed by formulation of both plain and aluminium adjuvanted sIPV. The final products met the quality criteria, were immunogenic in rats, showed no toxicity in rabbits and could be released for testing in the clinic. Concluding, sIPV was developed to manufacturing scale. The technology can be transferred worldwide to support post polio-eradication biosafety goals.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Postscript relating to new allegations made by Edward Hooper at The Royal Society Discussion Meeting on 11 September 2000

At The Royal Society Discussion Meeting, Origins of HIV and the AIDS epidemic, which this issue records, Edward Hooper added two new 'smoking guns' to the accusations published previously in The river. These were proposed as conclusive evidence for the hypothesis that simian immunodeficiency virus-contaminated CHAT polio vaccine caused the HIV-1 group M epidemic. We have investigated the facts in relation to these 'smoking guns'.     

Properties of recombinant hepatitis B vaccine

A large-scale purification method for hepatitis B surface antigen produced in a recombinant yeast (Saccharomyces cerevisiae) was established. The resulting HBsAg was greater than 99% pure and suitable for vaccine use. The yeast-derived HBsAg was structurally and biochemically similar to plasma-derived HBsAg. The anti-HBs antibody producing potency of the yeast-derived vaccine in mice was significantly higher than that of the plasma-derived vaccine. The yeast-derived vaccine induced protective antibody against hepatitis B virus of either adr or ayw subtype in a chimpanzee efficacy study. These observations demonstrate the usefulness of the yeast-derived vaccine as a second-generation hepatitis B vaccine.     

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.     

Polio vaccine and retroviruses

In this paper we consider the main steps in the process of manufacture of oral polio vaccine and assess the probable clearance factor for HIV retrovirus at each step. We conclude that the processes employed would have eliminated retrovirus contamination for all practical purposes.     

Clinical Surveillance After Feeding Oral Attenuated Live Polio Vaccine

During widespread administration of oral poliomyelitis vaccine in the United States and Canada, a number of neurological conditions occurring within 30 days of vaccine administration were reported. After careful investigation, 11 cases of paralytic poliomyelitis in the United States and four cases in Canada have been accepted as being most probably vaccine-associated.The case of a 35-year-old man who developed paralytic poliomyelitis 17 days after taking oral vaccine is reported. Type III Poliovirus was isolated from his stools, and subsequent virological investigation of this virus strain suggested that it most likely was the attenuated strain. The McBride test gave an NK value of 90 and the rct/40 marker was positive. A rise in Type III antibodies was found in the patient''s serum, and increased neurovirulence was demonstrated by intracerebral inoculation of monkeys.Since many cases of neurological involvement have not been accepted as vaccine-associated because of the lack of adequate early investigations, active clinical surveillance after oral polio vaccine administration is urged, and appropriate studies should be carried out in suspect neurological complications.     

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.