Enteroviruses in the XX and XXI centuries

The modern view of the role of enteroviruses in the eradication of poliomyelitis is presented. Enteroviruses were discovered in the XX century. In the 1950s they caused great epidemics of poliomyelitis and serous meningitis in many countries of the world. The introduction of oral poliomyelitis vaccine (OPV) into medical practice made it possible to eliminate the epidemics of poliomyelitis in a short time. Poliomyelitis morbidity was reduced to sporadic cases and in a number of regions disappeared. OPV produced non-specific influence also on the epidemics of serous meningitis, as well as on a case incidence. The eradication of poliomyelitis viruses and the cessation of immunization with OPV will not result in eradication of paralytic diseases. Paralytogenic viruses of 20 serotypes circulate in nature, and some of these viruses are capable of causing the outbreaks of severe paralytic diseases. The authors propose either to retain immunization with OVP as tour immunizations with monovaccine of type 2, or to create new live enterovirus vaccines on the basis of avirulent enterovirus strains.     

No evidence for prolonged excretion of polioviruses in persons with residual paralytic poliomyelitis in Ethiopia, Pakistan and Guatemala.

Persons who have developed acute flaccid paralysis following infection with wild-type polioviruses or vaccine-associated paralytic poliomyelitis usually excrete polioviruses for only a few weeks. However, some patients with paralytic poliomyelitis have had prolonged excretion of polioviruses for periods of up to 10 years after onset of disease. Most prolonged excretors have been identified in industrialized countries. We studied 348 patients 2-28 years old in Ethiopia, Pakistan and Guatemala with residual paralytic poliomyelitis to determine if they had IgA or IgG deficiency or persistent poliomyelitis excretion at least 1 year after onset of disease. None of the 348 affected individuals had IgG deficiency or persistent poliovirus excretion. One child had borderline low serum IgA concentration. Since we did not study children under 2 years of age, persons born with IgG deficiency disorders may have died in developing countries where replacement immunoglobulin therapy is not readily available. Nevertheless, persistent poliovirus excretion among persons 2 years of age and older with residual paralytic poliomyelitis is uncommon in developing countries.     

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.     

Vaccine preventable viral diseases in developing countries

There are several viral infectious diseases with a high impact on developing countries which can be prevented by immunization with existing vaccines. The most important are poliomyelitis, measles, hepatitis B and yellow fever. Vaccines against poliomyelitis and measles used within the framework of the WHO/Expanded Programme on Immunization prevent about 1.4 million deaths from measles and 360,000 cases of paralytic polio per year in developing countries, but about 1.5 million measles' deaths and 200,000 cases of paralytic polio still occur. Hepatitis B infection and its sequelae are responsible for over 50 million infections and one million deaths annually. Highly effective hepatitis B vaccines are now available and the price of these vaccines for the developing world has fallen dramatically. Despite the availability of a safe and efficacious yellow fever vaccine since 1937, 5400 cases of this disease with 3200 deaths were reported in Africa and South America from 1986 to 1988. Because of the efficacy of existing vaccines and the lack of animal reservoirs or vectors, systematic vaccination programmes within the framework of the Expanded Programme on Immunization (EPI) could theoretically eliminate and even eradicate poliomyelltis, measles and hepatitis B. Many different obstacles need to be overcome before these goals are realized.This paper was presented at the IUMS Symposium on New Developments in Diagnosis and Control of Infectious Diseases held in conjunction with the Eighth International Congress of Virology, Berlin, Germany, 24–31 August 1990.     

Poliomyelitis and vaccination strategy in Russian Federation in post-certification period

Immunization schedules implemented in various countries by using poliovirus vaccines are presented. Approaches to prevent development of vaccine associated paralytic poliomyelitis and risk groups for this infection are discussed. In recent years poliomyelitis morbidity situation in the European region has become more complex, with the example of poliomyelitis outbreak in Tajikistan in 2010. The resulting problem of protection of Russian against emergence and spread of poliomyelitis caused by wild type virus is discussed.     

HIV vaccines: a global perspective

Twenty years after its recognition, HIV/AIDS has become the most important infectious disease globally and the leading cause of death in Africa. A preventive vaccine represents the best long-term hope for its control. The development of such a vaccine, however, has encountered a number of scientific challenges, including the lack of information on immune correlates of protection, the limitations in our understanding of the relevance of primate protection experiments in relation to vaccine-induced protection in humans, and the significance of genetic and immunologic variability of HIV strains for potential vaccine efficacy. Despite these uncertainties, the first phase I trial of an HIV vaccine was conducted in the United States in 1987. Since then more than 30 candidate vaccines have been tested in over 70 phase I/II clinical trials in both industrialized and developing countries. The first HIV vaccine trial in a developing country was conducted in 1993, six years after the first trial in the United States. Since then eighteen phase I/II trials and one phase III trial have been or are being conducted in developing countries, and additional phase II and III trials are planned to start in 2003. Most of these initial trials have been conducted in Thailand, but more recently trials have been initiated in Africa, Latin America and the Caribbean. Over the past years, the HIV vaccine development effort has followed three major overlapping paradigms. The first "wave" of candidate vaccines aimed at inducing neutralizing antibodies. The second wave focused on stimulation of CD8+ T-cell responses. The current "wave" of HIV vaccine research is aimed at optimizing both humoral and cell-mediated immune responses. The first generation of candidate vaccines (based on the HIV envelope protein) entered phase III efficacy evaluation in 1998, and definitive results from these trials will become available in 2003. Plans to ensure wide access to future HIV vaccines must be developed well in advance.     

Is poliomyelitis a serious problem in developing countries?--lameness in Ghanaian schools.

A postal survey of lameness in schools throughout Ghana showed an estimated prevalence of lameness attributable to poliomyetitis of 5-8 per 1000 school-aged children and an estimated mean annual incidence of paralytic poliomyelitis of 23 per 100 000 population. Official reported incidence rates range from 0-1 to 2-1 per 100 000 population, indicating that at least 90% of cases are not reported. No evidence of epidemics was found to account for these high rates. These suggest that mean annual incidence rates in tropical endemic countries have always been as great, if not greater, than those experienced by temperate countries during epidemic periods in the twentieth century and that the total number of cases of paralytic poliomyelitis occurring in the world each year has been reduced by only 25% since the advent of polio vaccine. Immunisation against poliomyelitis must have a high priority in Ghana and other tropical countries where the disease is endemic.     

Helicobacter pylori vaccine development and use: a cost-effectiveness analysis using the Institute of Medicine Methodology

Background. Prophylactic vaccination has been suggested as a better strategy than antibiotics to control Helicobacter pylori infection. We evaluated the cost-effectiveness (CE) of H. pylori vaccine development and use in the United States and developing countries, using a method developed by the Institute of Medicine (IOM).
Methods. The IOM model includes costs of vaccine development, vaccination program, and averted medical treatments; morbidity and mortality prevented; expected efficacy and use; and proportion of disease that is vaccine-preventable. The model employs infant mortality equivalence (IME) to estimate disease burden; with IME, the societal cost of infection-related morbidity is expressed as equivalent to a specific rate of infant deaths. We tested model assumptions by univariate sensitivity analyses.
Results. In the United States, H. pylori vaccine would save 1,176 IME and would cost $58.71 million (1997 dollars) annually, yielding a CE ratio of $49,932 per IME; the health benefits would exceed all IOM-studied vaccines, even when efficacy dropped to 55%. H. pylori vaccine could be cost-saving if priced at less than $60 per course. In developing countries, H. pylori vaccine would rank unfavorably both in terms of health benefits (33,518 IME) and costs ($5,254 million). None of the changes in assumptions improved significantly the H. pylori vaccine's ranking relative to other IOM-studied vaccines.
Conclusions. Compared to other vaccines evaluated in the IOM study, H. pylori vaccine warrants public resource allocation for accelerated development and use in the United States but not for use in developing countries.     

Mechanism of Injury-Provoked Poliomyelitis

Skeletal muscle injury is known to predispose its sufferers to neurological complications of concurrent poliovirus infections. This phenomenon, labeled “provocation poliomyelitis,” continues to cause numerous cases of childhood paralysis due to the administration of unnecessary injections to children in areas where poliovirus is endemic. Recently, it has been reported that intramuscular injections may also increase the likelihood of vaccine-associated paralytic poliomyelitis in recipients of live attenuated poliovirus vaccines. We have studied this important risk factor for paralytic polio in an animal system for poliomyelitis and have determined the pathogenic mechanism linking intramuscular injections and provocation poliomyelitis. Skeletal muscle injury induces retrograde axonal transport of poliovirus and thereby facilitates viral invasion of the central nervous system and the progression of spinal cord damage. The pathogenic mechanism of provocation poliomyelitis may differ from that of polio acquired in the absence of predisposing factors.     

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.     

Scleroma of the Nose and Pharynx

Scleroma of the respiratory tract was first recognized just over a century ago. The disease is endemic in a number of North African, Central American and Latin American countries. However, it has been only rarely seen in the United States. The progression of scleroma takes place through three stages. The first stage of rhinitis has an early catarrhal phase which progresses to one of atrophic rhinitis. The second stage is seen as a proliferative granulomatous growth which obliterates the nasal fossae. The third cicatricial stage is usually accompanied by pronounced scarring and retraction of the tissues involved.Because of the increased ease of international travel by both sea and air, more cases can be expected to occur in the United States. This paper is presented to alert physicians to suspect scleroma in any case of granulomatous disease of the respiratory tract.     

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.     

Outside Europe. Is poliomyelitis a serious problem in developing countries?--the Danfa experience.

Children were examined for lameness in the Danfa Project district of rural Ghana to assess the impact of endemic poliomyelitis and to test a widely held hypothesis that paralytic poliomyelitis is relatively rare in such districts (less than 1 per 1000 children affected). The observed prevalence of lameness attributable to poliomyelitis was 7 per 1000 school-aged children, and the annual incidence is estimated to be at least 28 per 100 000 population. Although no evidence for an epidemic was found, these rates are comparable with those in the USA and Europe during the years of severe epidemics and indicate that a high price is being paid in the Danfa district for the natural acquisition of immunity. As a result, immunisation against poliomyelitis has been given high priority. A teacher questionnaire was also tested for use in postal surveys as a rapid means of estimating the prevalence of lamenes attributable to poliomyelitis in countries with a reasonable network of primary schools.     

Impact of vaccination on the infectious diseases epidemiology: example of pertussis

Several vaccines are now routinely used since fifty years in different developed countries. Their principal impact has been to decrease morbidity and mortality of the infectious diseases they are targeting. One disease, smallpox, is eradicated, poliomyelitis will be soon, diphteria is controlled in several countries but pertussis is still endemic although an efficacious vaccine was used. Why? Pertussis is an example of an infection for which the immunity of the population has changed after the introduction of generalized vaccination with killed whole cell pertussis vaccines, from a natural immunity due to infection to different types of vaccine-induced immunity. These different types of immunity have changed the protection against infection, disease and transmission. The impact of the generalized vaccination in a human population has been an important change in the epidemiology of the disease. In fact, a child-to-child transmission observed before the introduction of vaccination is now replaced by an adolescent-adult to infant transmission. The major consequence is an increase in the mortality and morbidity in non vaccinated infants mostly contaminated by their parents. Researches undertaken on the agent of the disease, the bacterium, Bordetella pertussis, conducted to the development of subunits vaccines, efficacious and better tolerated by infants than whole-cell vaccines. Many developed countries decided to change vaccines but also to add vaccine boosters for adolescents and adults in order to stop the transmission of the disease to infants. However, even after 15 years of studies in many countries, pertussis is still underestimated in adults and generalized adult vaccination remains difficult. The new goal now is to give information to medical students and health care workers in general in order to increase adolescent and adult's vaccination coverage.     

Historical aspects of the early Soviet/Russian manned space program.

Human spaceflight was one of the great physiological and engineering triumphs of the 20th century. Although the history of the United States manned space program is well known, the Soviet program was shrouded in secrecy until recently. Konstantin Edvardovich Tsiolkovsky (1857-1935) was an extraordinary Russian visionary who made remarkable predictions about space travel in the late 19th century. Sergei Pavlovich Korolev (1907-1966) was the brilliant "Chief Designer" who was responsible for many of the Soviet firsts, including the first artificial satellite and the first human being in space. The dramatic flight of Sputnik 1 was followed within a month by the launch of the dog Laika, the first living creature in space. Remarkably, the engineering work for this payload was all done in less than 4 wk. Korolev's greatest triumph was the flight of Yuri Alekseyevich Gagarin (1934-1968) on April 12, 1961. Another extraordinary feat was the first extravehicular activity by Aleksei Arkhipovich Leonov (1934-) using a flexible airlock that emphasized the entrepreneurial attitude of the Soviet engineers. By the mid-1960s, the Soviet program was overtaken by the United States program and attempts to launch a manned mission to the Moon failed. However, the early Soviet manned space program has a preeminent place in the history of space physiology.     

Molecular biology and the control of viral vaccines

Abstract The live attenuated vaccines against poliomyelitis developed by Sabin are among the safest and most effective antiviral vaccines in current use and have eliminated poliomyelitis as a public health problem in many countries. They form the main basis of the WHO intention to eliminate poliomyelitis from the world by the year 2000, and the molecular basis of their attenuated phenotype and some of its virological consequences are increasingly clear. Nonetheless, the data reviewed here show how poorly understood their mechanism of action is in use. Our studies raise the possibility of in vitro neurovirulence tests and may help to identify features of particular importance in the attenuation of the virus for human rather than simian recipients. On the other hand it is clear that when a live virus is used as a vaccine it is not possible to control it in the same way that genetically engineered products may be controlled in so far as replication in the recipient makes it possible for the live vaccine strain to alter in ways which may or may not be undesirable.     

Molecular biology and the control of viral vaccines

The live attenuated vaccines against poliomyelitis developed by Sabin are among the safest and most effective antiviral vaccines in current use and have eliminated poliomyelitis as a public health problem in many countries. They form the main basis of the WHO intention to eliminate poliomyelitis from the world by the year 2000, and the molecular basis of their attenuated phenotype and some of its virological consequences are increasingly clear. Nonetheless, the data reviewed here show how poorly understood their mechanism of action is in use. Our studies raise the possibility of in vitro neurovirulence tests and may help to identify features of particular importance in the attenuation of the virus for human rather than simian recipients. On the other hand it is clear that when a live virus is used as a vaccine it is not possible to control it in the same way that genetically engineered products may be controlled in so far as replication in the recipient makes it possible for the live vaccine strain to alter in ways which may or may not be undesirable.     

我国宫颈癌疫苗市场分析及对策研究*

宫颈癌Cervical cancer是最常见的妇科恶性肿瘤,是威胁女性健康的第二大恶性肿瘤。宫颈癌疫苗是预防宫颈癌发病的有效途径。2019年以前葛兰素史克(GSK)和默沙东(MSD)垄断了全球宫颈癌疫苗药物市场。虽然国内宫颈癌疫苗起步较晚,但在国内创新政策驱动下,20种疫苗已进入临床阶段,特别是由厦门万泰联合厦门大学研发的馨可宁于2020年4月获批上市,它是我国首个自主研发、全球第三个的宫颈癌疫苗。相比较欧美等发达国家,我国在宫颈癌疫苗推广力度上还有较大差距,我国9~45岁女性的HPV疫苗接种率不足0.05%。面对HPV疫苗接种覆盖率低,提出了优化HPV疫苗审评审批流程、将HPV疫苗纳入国家免疫规划、提高女性对HPV疫苗的认识等对策建议。     

The Sociopolitical Status of U.S. Naturopathy at the Dawn of the 21st Century

Naturopathic medicine in the United States had its inception around the turn of the 20th century. Subsequently, it underwent a process of relatively rapid growth until around the 1930s, followed by a period of gradual decline almost to the point of extinction due to biomedical opposition and the advent of "miracle drugs." Because its therapeutic eclecticism had preadapted it to fit into the holistic health movement that emerged in the 1970s, it was able to undergo a process of organizational rejuvenation during the last two decades of the century. Nevertheless, U.S. naturopathy as a professionalized heterodox medical system faces several dilemmas as it enters the new millennium. These include (1) the fact that it has succeeded in obtaining licensure in only two sections of the country, namely, the Far West and New England; (2) increasing competition from partially professionalized and lay naturopaths, many of whom are graduates of correspondence schools; and (3) the danger of cooptation as many biomedical practitioners adopt natural therapies.     

The practice of health risk assessment in the united states (1975–1995): How the U.S. and other countries can benefit from that experience

The process of quantitatively predicting the likelihood of an adverse response in humans or wildlife due to exposure to one or more chemicals is collectively known as environmental risk assessment. Quantitative risk assessment has been practiced in the United States and Canada for nearly 20 years and is the basis for most environmental and many occupational health regulations in North America. However, only since 1990 has it begun to receive serious consideration in Europe, Australia, Asia, and other regions. This paper reviews the historical evolution of health risk assessment in the United States and the scientific shortcomings in the process that have been introduced due to various regulatory policies. Despite these limitations and the reluctance of some countries to implement risk‐based policies, risk assessment will undoubtedly grow in importance within the international arena as other countries search for an ideal balance between cost and risk reduction. With the emergence of risk analysis as an international tool for understanding environmental issues, several improvements to the risk assessment process are recommended here that the United States and other countries could immediately incorporate into hazard identification, dose‐response and exposure assessments, and risk characterization. Examples of these improvements include use of a weight‐of‐evidence approach, physiologically‐based pharmacokinetic (PB‐PK) modelling, Monte Carlo techniques, and uncertainty analyses. These recommendations could, if coupled with an understanding of the historical experience in the United States, lead to superior environmental risk assessment policies for all countries as they enter the 21st century.