No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Abstract
Over the past half-century, global use of highly effective vaccines against poliomyelitis brought this disease to the brink of elimination. Mounting evidence supports the argument that a high level of population immunity must be maintained after wild poliovirus circulation is stopped to preserve a polio-free status worldwide. Shifting factors in the risk-benefit-cost equation favor the creation of new poliovirus vaccines for use in the foreseeable future. Genetically stable attenuated virus strains could be developed for an improved oral poliovirus vaccine, but proving their safety and efficacy would be impractical owing to the enormous size of the clinical trials required. Novel versions of inactivated poliovirus vaccine that could be used globally should be developed. An improved inactivated poliovirus vaccine must be efficacious, inexpensive, safe to manufacture and easy to administer. Combination products containing inactivated poliovirus vaccine and other protective antigens should become part of routine childhood immunizations around the world.
... The first group, the attenuated vaccines are created by adapting living organisms to grow in conditions that attenuate or weaken their virulence (Ulmer et al., 2006). However, attenuated microorganisms are often either too attenuated to induce a long-lasting intestinal immunity, still have residual virulence resulting in clinical signs or are genetically instable (Ehrenfeld et al., 2009). A number of strategies are now available for dealing with those instability issues, like reverse genetics, recombination, deletion mutants, codon deoptimization and control of replication fidelity (reviewed by Plotkin et al., 2009 (Hackett 1990;Mestecky et al., 2008;Panicali and Paoletti 1982), into which genes from pathogens are inserted and from which those genes come to expression. ...
... The oral route results in the induction of antibody and cell-mediated immune responses at the gut-associated lymphoid tissues (GALT), but often also at the systemic level (Seo et al., 2002;Verdonck et al., 2004a). Live attenuated microorganisms replicating in the gut are used in commercial oral vaccines (Ehrenfeld et al., 2009;Levine 2000;Soares-Weiser et al., 2010). However, these microorganisms are often either too attenuated to induce a long-lasting intestinal immunity or still have residual virulence resulting in clinical signs. ...
... Commercial oral vaccines that are available today mainly use live attenuated microorganisms replicating in the gut (Levine 2000;Soares-Weiser et al., 2010). The use of live vaccines involves potential risks (Ehrenfeld et al., 2009) and therefore, non-replicating oral vaccines are an interesting alternative. Nevertheless, the main issue for these vaccines is the induction of oral tolerance instead of a protective immunity. ...
Even with use of modern-day knowledge and techniques, still no efficient vaccines exist
against a lot of diseases. Most infectious diseases are caused by pathogens that colonize
and/or invade the host at mucosal surfaces. For an effective protection of the host,
pathogen-specific secretory IgA (SIgA) is required at the site of infection. This mucosal
immunity prevents the pathogens to colonize and/or invade the mucosa. Nonetheless, most commercial vaccines are delivered systemically by injection and although they elicit a strong systemic immune response, only a weak pathogen-specific mucosal immunity sometimes appears. In contrast, vaccination at mucosal sites can lead to protective mucosal immunity. However, formulation of mucosal vaccines is difficult and the progress in development has been rather slow. In this thesis, we evaluated new strategies for the oral immunization of pigs by directly targeting soluble antigens to the intestinal mucosa.
The F4ac fimbriae of enterotoxigenic Escherichia coli (ETEC) are one of the unique molecules that induce an immune response after oral immunization. This immune response requires the presence of the F4ac receptor (F4acR), as oral immunization of F4acR negative piglets with F4ac fimbriae does not result in the induction of an F4ac-specific mucosal immune response. Recently, our group identified porcine aminopeptidase N (pAPN) as a novel receptor for F4ac+ ETEC. In this thesis, we evaluate the use of APN as target for the delivery of oral vaccines. Moreover, two additional approaches were used to orally immunize piglets, i.e. maltose-binding protein (MBP) as carrier for antigens and porous pellets containing F4ac fimbriae.
Chapter 1 reviews the current knowledge of the intestinal mucosal immune system, antigen uptake in the gut, oral vaccination and ways to enhance the immune response. In addition, background information is provided about APN and MBP.
Chapters 3 to 7 describe the experimental work, which is subdivided into two parts. The first part deals with APN as target to obtain a mucosal immune response, whereas the second part evaluates the use of MBP as antigen carrier and targeting molecule and the use of porous pellets for oral immunization of pigs.
Following main questions were addressed:
1) Can APN be used as target for the delivery of oral vaccines?
2) Is the difference between F4acR positive and negative pigs caused by a difference in APN expression on protein level?
3) Is MBP able to target conjugated antigens towards the GALT?
4) Can oral vaccination with porous pellets loaded with F4ac fimbriae improve the
immune response against F4ac?
In Chapter 3 we determined if antibodies against pAPN are taken up by a receptor-mediated process and induce an anti-pAPN antibody-specific immune response when given orally, similar to the response against F4ac fimbriae. First the adhesion of the pAPN-specific antibodies to pig enterocytes was demonstrated in vitro by using a pAPN-transfected cell line (BHK-pAPN) as well as in vivo using intestinal loops. In the next step, pigs were orally immunized with purified antibodies against pAPN (anti-pAPN) or with purified rabbit IgG as negative control. The oral administration of anti-pAPN antibodies elicited a strong immune response in the pigs, even in the absence of the mucosal adjuvant cholera toxin (CT). Strong serum IgA, IgG, and IgM responses could already be observed after a primary immunization. Elevated levels of IgA, and IgG were found in the intestinal mucosa of the anti-pAPN and anti-pAPN + CT immunized animals nine days after the booster immunization. Furthermore, rabbit IgG-specific IgA ASCs were found in the LP in the anti-pAPN and anti-pAPN + CT immunized pigs, indicating the induction of a local IgA response against the pAPN-specific antibodies. These results and the fact that APN is present on the respiratory and intestinal epithelium of many species makes this molecule a promising candidate for the selective targeting of antigens towards the mucosal epithelium. However, in pigs it has not yet been demonstrated which epithelia of the digestive tract and respiratory tract express APN. This is necessary to know which mucosa can be targeted. In Chapter 4, the expression of pAPN was evaluated for F4acR positive and negative pigs. A difference in pAPN expression on protein level between F4acR positive and negative pigs would hamper the use of pAPN targeting in pigs. No difference in pAPN protein expression could be detected between the receptor positive and negative pigs. Either differences in APN glycosylation, in a molecule sterically hindering adhesion of F4ac fimbriae to the intestinal mucosa and/or other F4ac receptors involved in the initial binding could explain F4acR positive and negative pigs. We found a gradually increasing pAPN protein expression from duodenum to ileum. pAPN expression was not seen on the epithelium of the trachea, lung, tongue, oesophagus, stomach, large intestine (caecum and colon) and rectum. As a consequence, APN can be used as target for the delivery of molecules to the small intestine but not to the respiratory tract and large
intestine.
A good in vitro model is recommended for studying the pAPN-mediated uptake and transcytosis of antigens as well as for screening potential receptor ligands. The IPEC-J2 cell line, a pig intestinal epithelial cell line, is a good candidate as it is a relevant model for intestinal epithelial cells. But the IPEC-J2 cells express pAPN only in low amounts, not enough for pAPN-related binding studies. Therefore, in Chapter 5 we described the transfection of the IPEC-J2 cell line with pAPN. Flow cytometry was used to identify transfected cells which express pAPN by evaluating the binding of polyclonal rabbit pAPN-specific antibodies to the cells. Subsequently, the successfully transfected cells (IPEC-J2-pAPN) were positively selected using a FACSAria cell sorter and kept in continuous culture. In addition, a monoclonal antibody against pAPN was produced. Endocytosis of pAPN-specific antibodies by the IPECJ2- pAPN cells could be demonstrated, whereas no binding was observed using the IPEC-J2 cells. Vesicles containing anti-pAPN antibodies and clathrin colocalized during the anti-pAPN antibody internalization as seen for F4ac fimbriae and clathrin. This indicates that the IPECJ2- pAPN cell line is a promising tool for the in vitro study of pAPN-mediated binding and uptake.
In the second part of the experimental chapters, two additional approaches were used to
orally vaccinate piglets. Recent data suggest that the maltose-binding protein (MBP) may
potentiate antigen-presenting functions in immunized animals by providing intrinsic
maturation stimuli to dendritic cells via TLR4. The aim of Chapter 6 was to examine if an
MBP-specific immune response can be elicited by oral administration of MBP. In a first
experiment MBP or MBP + CT was orally administered to piglets and both the systemic and mucosal immune responses were examined. From the second immunization onwards, a significant serum antibody response could be observed in the MBP + CT group. Although no high systemic response was observed in the MBP-group, a local mucosal MBP-specific IgM response was observed in the jejunal Peyer’s patches. In a second experiment, MBPFedF was orally administered. A significant systemic response against MBP and a weaker response against FedF were found after oral administration of MBPFedF + CT. The presence of MBPspecific IgA ASC in the lamina propria indicated that a local intestinal immune response against MBP was induced. Our results suggest that MBP passes the epithelial barrier after oral administration to pigs, implying that MBP could act as a carrier and delivery system for targeting fused proteins to the intestinal immune system.
In Chapter 7, porous pellets consisting of Avicel PH 101 were evaluated for oral vaccination of suckling piglets with F4ac fimbriae. As the pellets consist of an interconnecting pore network, the F4ac fimbriae can penetrate inside the pellet what can offer a protection in the stomach and duodenum against acids, bile, enzymes antibodies and other glycoproteins binding to the fimbriae present. Fourteen F4acR+ pigs were selected, randomly divided into 3 groups and were orally immunized with either F4ac fimbriae in PBS, F4ac fimbriae in porous pellets or only PBS. Two weeks after the final vaccination, all animals were infected with a virulent F4ac+ ETEC strain. Although there were higher mucosal and serum IgA responses using porous pellets than soluble F4ac, a better protection against an induced infection could not be demonstrated. The F4ac+ ETEC excretion was lower in the pellet group compared to the soluble group until 6 days after the challenge but not in comparison with the PBS group. The duration of the faecal F4ac+ ETEC excretion was the same for both immunized groups and seemed 1 day shorter than for the PBS group. F4ac fimbriae are quite resistant to an acidic pH. Additional studies with more acid-sensitive antigens are needed to
determine if the pellet is able to protect and deliver such antigens more efficient to the
intestinal mucosa.
The final chapter (Chapter 8), presents the general conclusions and future perspectives. In
this thesis, we introduced APN as promising candidate for targeting of vaccine antigens
towards the mucosal epithelium and towards antigen presenting cells. We conclude that
APN can be used as target for the delivery of molecules to the small intestine, but not to the large intestine or the respiratory tract. No differences in pAPN expression could be detected between F4acR+ and F4acR- pigs, so APN targeting is applicable in both groups of pigs. The IPEC-J2-pAPN cell line as well as the pAPN monoclonal antibody can be used as tools for pAPN-related research. In addition, our results suggest that MBP can also pass the epithelial barrier after oral administration to pigs, implying that it is a potential carrier for targeting heterologous antigens towards the intestinal mucosal immune system.
... The first group, the attenuated vaccines are created by adapting living organisms to grow in conditions that attenuate or weaken their virulence (Ulmer et al., 2006). However, attenuated microorganisms are often either too attenuated to induce a long-lasting intestinal immunity, still have residual virulence resulting in clinical signs or are genetically instable (Ehrenfeld et al., 2009). A number of strategies are now available for dealing with those instability issues, like reverse genetics, recombination, deletion mutants, codon deoptimization and control of replication fidelity (reviewed by Plotkin et al., 2009 (Hackett 1990;Mestecky et al., 2008;Panicali and Paoletti 1982), into which genes from pathogens are inserted and from which those genes come to expression. ...
... The oral route results in the induction of antibody and cell-mediated immune responses at the gut-associated lymphoid tissues (GALT), but often also at the systemic level (Seo et al., 2002;Verdonck et al., 2004a). Live attenuated microorganisms replicating in the gut are used in commercial oral vaccines (Ehrenfeld et al., 2009;Levine 2000;Soares-Weiser et al., 2010). However, these microorganisms are often either too attenuated to induce a long-lasting intestinal immunity or still have residual virulence resulting in clinical signs. ...
... Commercial oral vaccines that are available today mainly use live attenuated microorganisms replicating in the gut (Levine 2000;Soares-Weiser et al., 2010). The use of live vaccines involves potential risks (Ehrenfeld et al., 2009) and therefore, non-replicating oral vaccines are an interesting alternative. Nevertheless, the main issue for these vaccines is the induction of oral tolerance instead of a protective immunity. ...
Ondanks de huidige kennis en knowhow bestaan er tegen vele ziekten nog steeds geen doeltreffende vaccins. Deze besmettelijke ziekten worden zeer dikwijls veroorzaakt door pathogenen die de mucosale oppervlakten koloniseren en/of binnendringen. Vaccinatie ter hoogte van de mucosa kan leiden tot een beschermende mucosale immuniteit maar de ontwikkeling van mucosale vaccins is moeilijk omdat voldoende antigenen de mucosale epitheellaag moet passeren zonder ziekte of tolerantie te veroorzaken. De F4ac fimbriae van enterotoxigene Escherichia coli (ETEC) behoren tot een beperkte groep van unieke moleculen die in staat zijn om een immuunrespons te induceren na orale immunisatie. Recent identificeerde onze onderzoeksgroep het varkens aminopeptidase N (pAPN) als nieuwe receptor voor F4ac+ ETEC. In dit proefschrift evalueerden we het gebruik van pAPN als doelwit voor de aflevering van orale vaccins. Bovendien werden twee bijkomende benaderingen gebruikt om biggen oraal te vaccineren, namelijk het gebruik van het maltose-bindend eiwit (MBP) als antigeendrager en poreuze pellets geladen met F4ac.
... 1 Historically, vaccines have eradicated diseases, such as smallpox, and nearly eliminated others, such as polio. 2,3 Vaccination can result in important outcomes, such as reducing disease incidence and complications. For example, widespread vaccination against hepatitis B virus (HBV) has greatly reduced chronic HBV infections and prevented an estimated 210 million new cases globally. ...
... This is because monovalent OPV does not have the potential to interact with different virus serotypes. Additionally, using E-IPV as a supplementary immunization source increases the seroconversion rates of the vaccines fivefold and enhances their immunogenicity (Ehrenfeld et al., 2009). ...
Throughout history, humanity has encountered several catastrophes, such as natural disasters and the emergence of countless contagious diseases. Poliomyelitis is one such disease. The initial instances of the sickness emerged in the 1940s, prompting health authorities and specialists to develop a vaccine to enhance children's resistance to the virus. Subsequently, polio workers worldwide are diligently endeavouring to raise awareness regarding the crucial significance of polio vaccination, particularly in the tribal regions of Pakistan. This is because the inhabitants of these areas are predominantly underprivileged and uneducated, resulting in their reluctance to vaccinate their children due to apprehensions about safety, as well as religious and misconceptions about the vaccine. The objective of these efforts is to ensure that every kid in Pakistan and Afghanistan receives appropriate immunization in order to halt the spread of the virus by the year 2025.
... Vaccines typically contain agents similar to disease-causing microorganisms, including: live attenuated vaccine(they are made by genetically engineering the target virus to stimulate the immune system and produce antibodies without causing disease) [63,64], protein-based vaccines (contains supramolecular structures or recombinant proteins that are similar to viral proteins) that known as virus-like particles (VLPs) and they stimulate the immune system to produce antibodies and memory cells [65]. These VLPs according to the lack of virus genetic material are safer than live attenuated vaccines [66,67]. ...
... OPV was preferred for its ease of administration (oral drops instead of intramuscular injection), superior immunogenicity, lower cost, and potential to immunize other individuals through vaccine strain community spread. However, the ability of the attenuated vaccine strain to mutate to a more virulent strain and cause vaccine-associated paralytic poliomyelitis has impeded eradication efforts (118,119). ...
Diagnostics and drug delivery technologies engineered for low-resource settings aim to meet their technical design specifications using strategies that are compatible with limited equipment, infrastructure, and operator training. Despite many preclinical successes, very few of these devices have been translated to the clinic. Here, we identify factors that contribute to the clinical success of diagnostics and drug delivery systems for low-resource settings, including the need to engage key stakeholders at an early stage, and provide recommendations for the clinical translation of future medical technologies.
... Clinically approved inactivated vaccines are developed against typhoid242 , cholera243 , hepatitis-A virus244 , plague245 , rabies246 , influenza247,248 , and polio249,250 . SARS-CoV-2 inactivated vaccines are in various developmental phases: Covi Vax (National Research Centre Egypt), Adjuvanted Inactivated Vaccine (The Scientific and Technological Research Council of Turkey), Recombinant NDV Vectored Vaccine (Laboratorio Avi-Mex), and Koçak-19 Inaktif Adjuvanlı COVID-19 Vaccine (Kocak Farma) presently in phase-I clinical trial; KoviVac (Chumakov Center) is in phase-II; vaccines QazVac (Kazakhstan RIBSP), Inactivated (Vero Cells) (Chinese Academy of Medical Sciences), Covaxin (Bharat Biotech), COVID-19 Inactivated Vaccine (Shifa Pharmed Industrial Co), BBIBP-CorV (Sinopharm (Beijing)), Inactivated (Vero Cells) (Sinopharm (Wuhan)), CoronaVac (Sinovac), ERUCOV-VAC (Health Institutes of Turkey), VLA2001 (Valneva), SARS-CoV-2 Vaccine (Vero Cells) (Minhai Biotechnology Co), KD-414 (KM Biologics Co Ltd) and FAKHRAVAC (MIVAC) (Organization of Defensive Innovation and Research) are in a phase-III clinical trial. ...
Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)‐induced COVID‐19 is a complicated disease. Clinicians are continuously facing difficulties to treat infected patients using the principle of repurposing of drugs as no specific drugs are available to treat COVID‐19. To minimize the severity and mortality, global vaccination is the only hope as a potential preventive measure. After a year‐long global research and clinical struggle, 165 vaccine candidates have been developed and some are currently still in the pipeline. A total of 28 candidate vaccines have been approved for use and the remainder are in different phases of clinical trials. In this comprehensive report, the authors aim to demonstrate, classify and provide up‐to‐date clinical trial status of all the vaccines discovered to date and specifically focus on the approved candidates. Finally, the authors specifically focused on the vaccination of different types of medically distinct populations.
... replication variants of the virus that cannot cause disease but can elicit a similar immune response to that seen in natural infections. It has been linked to genetic instability and the presence of residual virulence [30]. LAV has a simple production procedure that uses well-established Vero cells, which have been used for the research of vaccines for almost 40 years and were now the most widely accepted cell lineage for vaccine development by regulatory agencies. ...
Background
With the emergence of Corona virus Disease-2019, a novel worldwide health disaster is threatening the population. The WHO declared COVID-19 as a pandemic in December 2019, when it first surfaced in Hunan seafood market in Wuhan, South China, and quickly spread far and wide. Different corona virus variants are currently causing concern all across the world.
Main body
It has become critical for our scientists to develop a viable method to prevent infection or the pandemic from spreading globally. Antiviral medicines, oxygen therapy, and immune system stimulation are all used to treat the condition. SARS-CoV-2 undergoes mutation and due to evolutionary pressures, different mutant strains caused various symptoms in different geographical regions and the epidemic is spreading and becoming more fragile, posing a greater risk of mortality. Vaccines are tools to increase our immunity as a precaution, and increasing the global immunization rate can help improve the situation. Recent developments in the field of vaccine platforms are discussed here.
Short conclusion
Vaccines are of highest priority to control and eradicate the viral infectious disease COVID-19 more than any other protective solutions. A number of mutations have occurred and some variants such as alpha, beta, gamma, and delta, and it has now progressed to the new version Omicron, which is a variant of concern. Booster doses are anticipated to function as a barrier to the capacity of the most recent known variety, and more research is needed to determine how effective they will be. This page discusses various technologies employed in the field of COVID-19 vaccine, as well as potential barriers and recent developments in this field.
... New Approaches in Terms of Immunization It has been evident from the trials in many countries that the use of monovalent OPV instead of trivalent OPV for routine vaccination can reduce the risk of re-emergence of vaccine-derived paralytic poliomyelitis as there is no chance of interaction of the virus serotypes in monovalent OPV and also using E-IPV as a source of supplementary immunization also enhances the seroconversion rates of the vaccines manifold and provides increased immunogenicity. (Ehrenfeld, Modlin and Chumakov, 2009). ...
Humanity has faced numerous calamities, natural disasters, and even the outbreaks of numerous communicable diseases since the dawn of time, and poliomyelitis is one of these diseases. The first cases of the disease occurred in the 1940s, alerting the health authorities and experts to create a vaccine to improve children's immunity to the virus. Since then, polio workers all across the globe are trying their best to create awareness about the importance of polio vaccination which is especially needed in the tribal areas of Pakistan because the people living there are mostly backward and illiterate who do not vaccinate their children due to safety concerns as well as religious and general misbeliefs about the vaccine. The focus of these campaigns is to make sure that every child in Pakistan and Afghanistan is properly vaccinated to stop the transmission of the virus by the year 2022.
... This type of vaccination makes it possible to expose several specific epitopes of the pathogen to the immune system and reproduces the characteristics of an infection like the active pathogen, without developing the disease. These vaccines often require only one immunization because they induce a very strong immune response and the production of memory lymphocytes [7,8]. ...
... New vaccine preparations have to meet the following requirements: low cost, increased ability to induce an immune response in the mucous membranes and compliance with biosafety criteria [53]. ...
The dramatic history of the development and use of polio vaccines reflects the evolution of vaccine preparations under the influence of changing epidemiological conditions and socio-economic factors. The invention of two polio vaccines — the inactivated Salk vaccine and the live oral vaccine from Sabin strains, each with its own advantages and disadvantages — is on the list of the most significant medical achievements of the XX century. Over the past 50 years, these vaccines were used in various modalities, schemes, and combinations. As a result, poliomyelitis has been completely eradicated in almost all countries of the world. The sustained WHO-led efforts toward full eradication of the disease are expected to result in complete cessation of the virus circulation. In this case, the poliovirus, like the smallpox virus, will remain only in laboratories. However, it would be unreasonable to stop the vaccination even after the pathogen circulation has been stopped like it was in the case with the elimination of smallpox virus. Unlike the smallpox vaccination, vaccines against poliomyelitis will not lose their relevance in the near future because these two viruses significantly differ from each other in terms of biological and epidemiological characteristics. © 2019, Privolzhsky Research Medical University. All rights reserved.
... This significantly increased the global demand for IPV and required increase in manufacturing capacities for existing IPV manufacturers and new manufacturers to begin producing the vaccine. cIPV is made from highly virulent wild polioviruses (Mahoney, MEF-1, and Saukett strains for types 1, 2, and 3, respectively) (Ehrenfeld et al., 2009;Duintjer Tebbens et al., 2013). Use of the wild strains in vaccine manufacture requires very tight biosafety and biosecurity measures to prevent accidental or intentional release of the virus into the environment ((WHO) WHO, 2015b). ...
To address the biosafety and biosecurity concerns related to the manufacture of inactivated polio vaccine (IPV), several manufacturers started producing it from attenuated Sabin strains. Slight immunological differences between wild and attenuated strains create a challenge for testing IPV potency, which is defined as the content of protective D-antigen determined in an ELISA test. Some ELISA reagents selected for testing conventional IPV made from wild strains (cIPV) may not be suitable for testing Sabin IPV (sIPV). This paper describes an ELISA procedure using human monoclonal antibodies selected to capture equally well both wild and attenuated strains of poliovirus. A unique monoclonal antibody neutralizing all three serotypes of poliovirus was used as the detection antibody. The method was shown to detect only D-antigen of both conventional and Sabin IPV and to be strictly serotype-specific. The method is highly sensitive and robust and produces linear results in a wide range of concentrations. We have also found that reference standards used for measuring potency of cIPV and sIPV must be made from respective vaccines. This makes it impossible to cross-calibrate potency reagents made from heterologous vaccine and requires the establishment of a new unit to measure potency of sIPV that is different from conventional D-antigen unit.
... Depending on the extent of CNS damage, they can further be classified into three types: spinal, bulbar and bulbospinal forms [2]. Most patients recover in weeks to months after an acute disease, but residual motor deficits remain in about two-thirds of initially paralyzed patients, some experiencing minor debility while others from permanent, flaccid paralysis [40]. ...
p>Poliovirus is the pathogenic agent of paralytic poliomyelitis that belongs to the picornaviridae family. Poliomyelitis has an extended history dating over to the Egyptian eighteenth dynasty. It was recognized as distinct disease in the late nineteenth century when the world was ravaged by large number of outbreaks and epidemics in many countries. Paralytic Polio, the rarest but the most severe form of the disease, is characterized by acute flaccid paralysis of any or rarely both of the limbs. Increasing epidemics during the late 19th and 20th centuries lead to the initiation of a worldwide global effort for polio eradication in 1988, super headed by WHO and various other organizations. The launch of Global Polio Eradication Initiative together with the introduction of two polio vaccines resulted in 99% reduction of wild poliovirus cases worldwide while the total number of polio-endemic countries dropped from 24 countries in the year 2000 to only three countries in 2012; Afghanistan, Nigeria and Pakistan. This review will focus on the general biology of poliovirus, some historic and geographic epidemiological aspects of poliomyelitis eradication during the year 2000-2012 and also on the major failing factors associated with the efficiency of the vaccines to eradicate polio in Pakistan.</p
... Попытки обойти вышеуказанные проблемы предпринимаются при разработке нового поколения вакцин, которые будут использоваться после элиминации. Новые препараты должны соответствовать следующим принципам: низкая стоимость, повышенная способность вызывать иммунный ответ со стороны слизистых оболочек и соответствие требованиям биобезопасности [88]. Для создания новых живых вакцин необходимо использовать вирусы с повышенной генетической стабильностью, чтобы исключить вероятность реверсии вирулентности. ...
The history of polio vaccines and their use illustrates the concept of evolution of vaccines driven by changing epidemiological and socioeconomic conditions. The development of two vaccines against poliomyelitis – inactivated Salk vaccine (IPV) and live oral Sabin vaccine (OPV) – is among the most consequential achievements of prophylactic medicine of the past century. Each with their own strengths and weaknesses, they were used over the past 50 years in different settings and different regimens and combinations. This resulted in virtual elimination of the disease in almost the entire world with the exception of a few countries. Continuation of the eradication campaign coordinated by WHO may soon result in complete cessation of wild poliovirus transmission, and poliovirus may join smallpox virus in the club of extinct pathogens. However, unlike smallpox vaccination that was stopped after the interruption of virus circulation, vaccination against poliomyelitis will have to continue into the foreseeable future, due to significant differences in the nature and epidemiology of the viruses. This review provides the reasons for the need to maintain high population immunity against polioviruses, makes the case for developing a new generation of polio vaccines, and discusses their desirable properties as well as new vaccine technologies that could be used to create polio vaccines for the post-eradication environment.
... Depending on the extent of CNS damage, they can further be classified into three types: spinal, bulbar and bulbospinal forms [2]. Most patients recover in weeks to months after an acute disease, but residual motor deficits remain in about two-thirds of initially paralyzed patients, some experiencing minor debility while others from permanent, flaccid paralysis [40]. ...
p>Poliovirus is the pathogenic agent of paralytic poliomyelitis that belongs to the picornaviridae family. Poliomyelitis has an extended history dating over to the Egyptian eighteenth dynasty. It was recognized as distinct disease in the late nineteenth century when the world was ravaged by large number of outbreaks and epidemics in many countries. Paralytic Polio, the rarest but the most severe form of the disease, is characterized by acute flaccid paralysis of any or rarely both of the limbs. Increasing epidemics during the late 19th and 20th centuries lead to the initiation of a worldwide global effort for polio eradication in 1988, super headed by WHO and various other organizations. The launch of Global Polio Eradication Initiative together with the introduction of two polio vaccines resulted in 99% reduction of wild poliovirus cases worldwide while the total number of polio-endemic countries dropped from 24 countries in the year 2000 to only three countries in 2012; Afghanistan, Nigeria and Pakistan. This review will focus on the general biology of poliovirus, some historic and geographic epidemiological aspects of poliomyelitis eradication during the year 2000-2012 and also on the major failing factors associated with the efficiency of the vaccines to eradicate polio in Pakistan.</p
... While VAPP and cVDPV occurrences have greatly been reduced with IPV, the switch from OPV to IPV has been challenging due to multiple factors including supply shortages, higher production costs compared to OPV (see below), and administration (intramuscular) requiring a health care professional. [1][2][3] In addition, IPV requires a cold-chain to maintain efficacy and potency during storage and transport with losses observed at elevated temperatures (!25 C). 4 Currently, several strategies are being examined to produce an improved IPV that is efficacious, inexpensive, safe to manufacture, and easier to administer. From the bulk vaccine manufacturing perspective, a key strategy is to develop IPV from the attenuated polio strains (e.g., Sabin-IPV). ...
The worldwide switch to inactivated polio vaccines (IPV) is a key component of the overall strategy to achieve and maintain global polio eradication. To this end, new IPV vaccine delivery systems may enhance patient convenience and compliance. In this work, we examine NanopatchTM (a solid, polymer micro-projection array) which offers potential advantages over standard needle/syringe administration including intradermal delivery and reduced antigen doses. Using trivalent IPV (tIPV) and a purpose-built evaporative dry-down system, candidate tIPV formulations were developed to stabilize tIPV during the drying process and upon storage. Identifying conditions to minimize tIPV potency losses during rehydration and potency testing was a critical first step. Various classes and types of pharmaceutical excipients (∼50 total) were then evaluated to mitigate potency losses (measured through D-antigen ELISAs for IPV1, IPV2, and IPV3) during drying and storage. Various concentrations and combinations of stabilizing additives were optimized in terms of tIPV potency retention, and two candidate tIPV formulations containing a cyclodextrin and a reducing agent (e.g., glutathione), maintained ≥80% D-antigen potency during drying and subsequent storage for 4 weeks at 4˚C, and ≥60% potency for 3 weeks at room temperature with the majority of losses occurring within the first day of storage.
... This means that testing of new interventions (e.g., poliovirus antiviral compounds, new poliovirus vaccines) that require OPV use for demonstrating effectiveness or noninferiority must occur prior to OPV cessation. Recognizing this limited time window and the potential need for better poliovirus vaccines in the future, the GPEI and others continue to consider the possibility of developing new vaccines that combine the advantages of OPV and IPV [35,50,[60][61][62][63][64][65][66][67][68][69]. However, no existing studies provide quantitative estimates of the potential impact of new poliovirus vaccines to inform decisions related to further investments into new poliovirus vaccine development. ...
Aim:
To estimate the incremental net benefits (INBs) of a hypothetical ideal vaccine with all of the advantages and no disadvantages of existing oral and inactivated poliovirus vaccines compared with current vaccines available for future outbreak response.
Methods:
INB estimates based on expected costs and polio cases from an existing global model of long-term poliovirus risk management.
Results:
Excluding the development costs, an ideal poliovirus vaccine could offer expected INBs of US$1.6 billion. The ideal vaccine yields small benefits in most realizations of long-term risks, but great benefits in low-probability-high-consequence realizations.
Conclusion:
New poliovirus vaccines may offer valuable insurance against long-term poliovirus risks and new vaccine development efforts should continue as the world gathers more evidence about polio endgame risks.
... For these reasons, there have been repeated calls-for-action for new poliovirus vaccines in the past decade in 2005 and 2008 [4,9,10]. In response, a broad base coalition of institutions and manufacturers have made significant progress during the last decade in developing S-IPV, indicating that S-IPV is both an effective and economical option for interested manufacturers in developing countries. ...
The Global Polio Eradication Initiative (GPEI) has seen significant progress since it began in 1988, largely due to the worldwide use of oral poliovirus vaccine (OPV). In order to achieve polio eradication the global cessation of OPV is necessary because OPV contains live attenuated poliovirus, which in rare circumstances could re-gain wild poliovirus (WPV) characteristics with potential to establish transmission.
The GPEI endgame strategy for the period 2013–2018 recommends the globally synchronised sequential cessation of the Sabin strains contained in the OPV, starting with type 2 Sabin. The withdrawal of Sabin type 2 took place in April 2016, with the introduction of at least one dose of inactivated poliovirus vaccine (IPV) as a risk mitigation strategy. The introduction of IPV into 126 countries since 2013 has required a rapid scale-up of IPV production by the two manufacturers supplying the global public sector market. This scale-up has been fraught with challenges, resulting in reductions of 40–50% of initial supply commitments. Consequently, 22 countries will not be supplied until 2018, and another 23 countries will experience serious stock-outs.
In the last decade repeated calls-for-action were made to the global community to invigorate their vision and investment in developing “new poliovirus vaccines” including the development of IPV from less-virulent strains, such as Sabin-IPV (S-IPV). The conventional Salk-IPV production is limited to high-income industrialized-country manufacturers due to the containment requirements (i.e., high sanitation, low force-of-poliovirus-infection, and high population immunity). The use of Sabin strains in the production of S-IPV carries a lower biosafety risk, and was determined to be suitable for production in developing countries, expanding the manufacturing base and making IPV more affordable and accessible in the long term.
Significant progress in the S-IPV has been made since 2006. S-IPV is now licensed as S-IPV in Japan and as standalone S-IPV in China, demonstrating the feasibility of this vaccine. In addition, production process improvements can further reduce the cost of production. The latter are critical to the economic success of this vaccine in the global market. We summarize the progress made to date in S-IPV technology, the scientific data and economic evidence in support of S-IPV development.
... The two types of polio vaccines currently being used are the oral polio vaccine (OPV), a live attenuated virus, and the inactivated polio vaccine (IPV). IPV, while much safer than OPV with no risk of reversion to a disease-causing virus [4], must be injected more than once for efficacy [5]. This can be prohibitive to protection and eradication efforts, as studies in some regions of the world have found that coverage for a second dose of vaccines is much lower than that for the first dose [6]. ...
Vaccines are a critical clinical tool in preventing illness and death due to infectious diseases and are regularly administered to children and adults across the globe. In order to obtain full protection from many vaccines, an individual needs to receive multiple doses over the course of months. However, vaccine administration in developing countries is limited by the difficulty in consistently delivering a second or third dose, and some vaccines, including the inactivated polio vaccine (IPV), must be injected more than once for efficacy. In addition, IPV does not remain stable over time at elevated temperatures, such as those it would encounter over time in the body if it were to be injected as a single-administration vaccine. In this manuscript, we describe microspheres composed of poly(lactic-co-glycolic acid) (PLGA) that can encapsulate IPV along with stabilizing excipients and release immunogenic IPV over the course of several weeks. Additionally, pH-sensitive, cationic dopants such as Eudragit E polymer caused clinically relevant amounts of stable IPV release upon degradation of the PLGA matrix. Specifically, IPV was released in two separate bursts, mimicking the delivery of two boluses approximately one month apart. In one of our top formulations, 1.4, 1.1, and 1.2 doses of the IPV serotype 1, 2, and 3, respectively, were released within the first few days from 50mg of particles. During the delayed, second burst, 0.5, 0.8, and 0.6 doses of each serotype, respectively, were released; thus, 50mg of these particles released approximately two clinical doses spaced a month apart. Immunization of rats with the leading microsphere formulation showed more robust and long-lasting humoral immune response compared to a single bolus injection and was statistically non-inferior from two bolus injections spaced 1 month apart. By minimizing the number of administrations of a vaccine, such as IPV, this technology can serve as a tool to aid in the eradication of polio and other infectious diseases for the improvement of global health.
... Eradication of poliovirus was almost achieved using the trivalent polio vaccination. However, now, the monovalent oral polio vaccine (OPV) or inactivated polio vaccine (IPV) shall enable the complete eradication of polio (Ehrenfeld et al. 2009). Many live vaccines are in use for livestocks like bovine respiratory syncytial virus for cattle or calicivirus in cats. ...
The employment of live attenuated vaccines has a long-standing record in human and veterinary medicine. Most of the vaccines in current use were empirically developed during the last century. Today, due to the great advances in fields such as immunology and bioengineering, the rational development of live attenuated vaccines becomes increasingly feasible. Moreover, live vaccines can be used as carrier systems for heterologous antigens or therapeutic factors. In each case, the development of a recombinant live attenuated vaccine is a complex task where properties such as targeting specificity, antigen synthesis, antigen release, and safety aspects have to be integrated. A range of such recombinant vaccine candidates have successfully been tested in the clinics, but very few have been approved so far. In many cases, further optimization of such vaccines is necessary with regard to their efficacy and safety profiles. In the present chapter, we focus on current strategies which are employed for the development of new and the optimization of first generation recombinant live vaccines based on bacteria and viruses.
... Due to the lack of effective therapy against most flaviviruses, the focus on developing potential vaccines has escalated. Considering the increasing prevalence of WNV in the USA, as well as the globalization of DENV, development of successful vaccines is imperative for effectively preventing flaviviral-associated diseases (Chao et al. 2012;Ehrenfeld et al. 2009;Sutter et al. 2000). However, any such success requires further knowledge of flaviviral disease pathogenesis. ...
... [2] A cornerstone of the polio eradication strategy is the need to ensure high levels of routine immunization coverage with 3 doses of oral polio vaccine (OPV) in children <1 year at national, regional, and district levels. [3,4] Good routine OPV coverage reduces the incidence of polio and makes eradication feasible. The WHO through EPI has established a global target of at least 90% immunization coverage by 2000 for six diseases diphtheria, tetanus, whooping cough, tuberculosis, measles, and poliomyelitis. ...
... Depending on the extent of CNS damage, they can further be classified into three types: spinal, bulbar and bulbospinal forms [2]. Most patients recover in weeks to months after an acute disease, but residual motor deficits remain in about two-thirds of initially paralyzed patients, some experiencing minor debility while others from permanent, flaccid paralysis [40]. ...
Poliovirus is the pathogenic agent of paralytic poliomyelitis that belongs to the picornaviridae family. Poliomyelitis has an extended history dating over to the Egyptian eighteenth dynasty. It was recognized as distinct disease in the late nineteenth century when the world was ravaged by large number of outbreaks and epidemics in many countries. Paralytic Polio, the rarest but the most severe form of the disease, is characterized by acute flaccid paralysis of any or rarely both of the limbs. Increasing epidemics during the late 19 th and 20 th centuries lead to the initiation of a worldwide global effort for polio eradication in 1988, super headed by WHO and various other organizations. The launch of Global Polio Eradication Initiative together with the introduction of two polio vaccines resulted in 99% reduction of wild poliovirus cases worldwide while the total number of polio-endemic countries dropped from 24 countries in the year 2000 to only three countries in 2012; Afghanistan, Nigeria and Pakistan. This review will focus on the general biology of poliovirus, some historic and geographic epidemiological aspects of poliomyelitis eradication during the year 2000-2012 and also on the major failing factors associated with the efficiency of the vaccines to eradicate polio in Pakistan.
... Since Edward Jenner's discovery in the late 1700's that inoculation with the cowpox virus provided protection from smallpox infection, vaccines have emerged as one of the greatest public health tools in history. The last 60 years have established a golden age in the field of vaccinology, marked by events such as the eradication of smallpox by 1980 [1] and the development of polio vaccines in the 1950s, which have lead to near-eradication of the disease [2]. Despite the great success of these and other vaccines, there remain significant challenges for development of new vaccines against current global pandemics such as HIV and malaria. ...
Vaccines have drastically reduced the mortality and morbidity of many diseases. However, vaccines have historically been developed empirically, and recent development of vaccines against current pandemics such as HIV and malaria has been met with difficulty. The advent of high-throughput technologies, coupled with systems biological methods of data analysis, has enabled researchers to interrogate the entire complement of a variety of molecular components within cells, and characterize the myriad interactions among them in order to model and understand the behavior of the system as a whole. In the context of vaccinology, these tools permit exploration of the molecular mechanisms by which vaccines induce protective immune responses. Here we review the recent advances, challenges, and potential of systems biological approaches in vaccinology. If the challenges facing this developing field can be overcome, systems vaccinology promises to empower the identification of early predictive signatures of vaccine response, as well as novel and robust correlates of protection from infection. Such discoveries, along with the improved understanding of immune responses to vaccination they impart, will play an instrumental role in development of the next generation of rationally designed vaccines.
Copyright © 2015. Published by Elsevier Ltd.
... The currently available polio vaccines, introduced in the middle of the 20th century, are among the most successful and widely used vaccines ever produced [1]. For the 1st inactivated polio vaccine (IPV) preparation, virus production was done in roller bottles: poliovirus (PV) was propagated on primary monkey testis or kidney tissue in Medium 199 [2] followed by clarification through centrifugation and storage at −20 • C. ...
Polio is expected to be eradicated within only a few years from now. Upon polio eradication, the use of oral polio vaccines, which can cause circulating and virulent vaccine derived polio viruses, will be stopped. From this moment onwards, inactivated polio vaccines (IPV) will be used for worldwide vaccination against polio. An increased demand for IPV is thus anticipated. As a result, process development studies regarding the IPV production process, developed in the 1960s, have intensified. Studies on yield optimization aiming at costs reduction as well as the use of alternative polio viruses, which are more biosafe for manufacturing, are actual. Here our strategy to setup a new IPV production process using attenuated Sabin polio virus strains is presented. Moreover, aspects on reduction of the costs of goods and the impact of process optimization on sIPV costs are reviewed.
Copyright © 2015. Published by Elsevier Ltd.
... En este sentido la extensión de una cepa cVDPV1 en Minnesota en 2005 en una población no vacunada 71 refuerza la idea de que la mejor forma de enfrentarse a estos hechos es conseguir una amplia y correcta cobertura vacunal, si es baja, los poliovirus de la polio oral pueden circular y evolucionar a tipos con neurotoxicidad 39 . Así mismo se estima que es necesario conseguir nuevas vacunas inactivadas 72 u orales más estables genéticamente 39,73 . ...
Although the WHO original target date for the global eradication of poliomyelitis was the year 2000 -thanks to vaccination and institutional, public and private, resources for that purpose-, in 2013 the disease remained endemic in three countries, Afghanistan, Pakistan and Nigeria, and some cases were described in five others. The circulation of wild type 1 poliovirus in Israel, Gaza and the West Bank and the cases in Syria were a wakeup call, as at that time there were polioviruses derived from the oral vaccine that are still circulating among the human population and can cause the development of the disease. Travelling "from" and "to" endemic areas are factors to consider in poliovirus exportation and in its spread when it reaches areas with poor immunogenicity. Wars, terrorism, intolerance, lack of culture and proliferation of anti-vaccine groups and the rise of the anti-vaccination movement are important factors in the maintenance and expansion of the virus and in the "non-vaccination" against it. Based on the international situation to date, the Emergency Committee of WHO met in May 2014 to address the problem. It is still necessary to enhance the knowledge of the disease and its agent. In the first case to perform a differential diagnosis of flaccid paralysis and to continue vaccination programs, and in the second case to keep studying and looking for the poliovirus in environmental samples, which is a model for the study of many other viruses.
Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.
... Polio eradication efforts have been highly successful in most areas of the world, but circulation of wild polioviruses (WPVs) persists in some countries despite vigorous efforts and administration of multiple doses of polio vaccines to a high proportion of children [1]. The failure to eliminate WPV transmission in polioendemic countries is due in part to the lower immunogenicity of trivalent oral poliovirus vaccine (tOPV) in some countries [2]. Three doses of tOPV have induced >95% immune response rates for all 3 poliovirus types in infants from industrialized countries, compared with 73% (range, 36%-99%) for type 1 poliovirus, 89% (range, 71%-100%) for type 2 poliovirus, and 70% (range, 40%-99%) for type 3 poliovirus in some developing countries [3,4]. ...
Background. Polio eradication efforts have been hampered by low responses to trivalent oral poliovirus vaccine (tOPV) in some developing countries. Since stomach acidity may neutralize vaccine viruses, we assessed whether administration of a buffer solution could improve the immunogenicity of tOPV.
Methods. Healthy infants 4–6 weeks old in Sylhet, Bangladesh, were randomized to receive tOPV with or without a sodium bicarbonate and sodium citrate buffer at age 6, 10, and 14 weeks. Levels of serum neutralizing antibodies for poliovirus types 1, 2, and 3 were measured before and after vaccination, at 6 and 18 weeks of age, respectively.
Findings. Serologic response rates following 3 doses of tOPV for buffer recipients and control infants were 95% and 88% (P = .065), respectively, for type 1 poliovirus; 95% and 97% (P = .543), respectively, for type 2 poliovirus; and 90% and 89% (P = .79), respectively, for type 3 poliovirus.
Conclusions. Administration of a buffer solution prior to vaccination was not associated with statistically significant increases in the immune response to tOPV; however, a marginal 7% increase (P = .065) in serologic response to poliovirus type 1 was observed.
Clinical Trials Registration. NCT01579825.
... Due to the lack of effective therapy against most flaviviruses, the focus on developing potential vaccines has escalated. Considering the increasing prevalence of WNV in the USA, as well as the globalization of DENV, development of successful vaccines is imperative for effectively preventing flaviviral-associated diseases (Chao et al. 2012;Ehrenfeld et al. 2009;Sutter et al. 2000). However, any such success requires further knowledge of flaviviral disease pathogenesis. ...
The flaviviruses dengue, West Nile, and Japanese encephalitis represent three major mosquito-borne viruses worldwide. These pathogens impact the lives of millions of individuals and potentially could affect non-endemic areas already colonized by mosquito vectors. Unintentional transport of infected vectors (Aedes and Culex spp.), traveling within endemic areas, rapid adaptation of the insects into new geographic locations, climate change, and lack of medical surveillance have greatly contributed to the increase in flaviviral infections worldwide. The mechanisms by which flaviviruses alter the immune and the central nervous system have only recently been examined despite the alarming number of infections, related deaths, and increasing global distribution. In this review, we will discuss the expansion of the geographic areas affected by flaviviruses, the potential threats to previously unaffected countries, the mechanisms of pathogenesis, and the potential therapeutic interventions to limit the devastating consequences of these viruses.
... Rhv-like 1 protein was located at aa residues 307-427 and has a mass of 13.7 kDa, rhv-like 2 at residues 571-728 with a mass of 17.9 kDa, and rhv-like 3 at residues 858-977 has a mass of 13.4 kDa (Fig. 1b). Viruses that encode three similar capsid proteins at the Nterminus of their polyproteins are non-enveloped plus-strand ssRNA animal viruses with icosahedral capsids (Ehrenfeld et al., 2009). An RNA helicase is predicted from residues 1,374-1,480. ...
The genomic sequence of a previously undescribed virus was identified from symptomless tomato plants (Solanum lycopersicum). The viral genome is a positive sense ssRNA molecule of 8,506 nucleotides. It is predicted to encode a single polyprotein of 314.5 kDa, which is subsequently processed into three coat protein components of 13.7, 17.9 and 13.5 kDa, and a viral replicase of approximately 207 kDa with conserved motifs for a helicase, a protease, and RNA-dependent RNA polymerase (RdRp). Pairwise analysis of the deduced amino acid sequence of the RdRp revealed that it shares closest identity with members of the family Iflaviridae, genus Iflavirus (19-47% identity). Evidence of replication in plants was detected by RT-PCR of the viral replicative strand, and short interfering RNAs (siRNAs) matching the virus. We propose the name Tomato matilda virus (TMaV), and further, propose that the genus Tomavirus (Tomato Matilda virus) be created within the family Iflaviridae. This is the first report of a plant-infecting virus resembling members of the Iflaviridae.This article is protected by copyright. All rights reserved.
... Similarly, four SIAs using monovalent OPV1 and bivalent OPV1/3 stopped the ROC 2010 outbreak (21), providing a robust population immunity that likely exceeded the relatively lower protection against PV1-RC2010. Sustained vaccination regimens potentially involving both IPV and OPV in polio-free regions aided by timely detection of WPV1 reintroductions through environmental and clinical surveillance will thus be necessary to combat the spread of variant viruses in the poliomyelitis eradication endgame (41). ...
Significance
In 2010, a large outbreak of poliomyelitis involving 445 laboratory-confirmed cases occurred in the Republic of Congo. The 47% case-fatality rate was unusually high. Outbreak severity was attributed to low immunization coverage but vaccine-mediated immunity against the outbreak virus was never investigated. We isolated the poliovirus type 1 responsible for the outbreak and located its evolutionary origins to Southeast Asia. Fatal cases showed evidence for previous vaccination against polioviruses and the outbreak virus was refractive against neutralization by monoclonal and vaccine-derived antibodies. This pointed to immune escape contributing to the severity of the outbreak. Sustained vaccination regimens in polio-free regions, together with clinical and environmental poliovirus surveillance will be necessary to combat antigenetically variant polioviruses in the poliomyelitis eradication endgame.
... To achieve global polio eradication, an (improved) IPV must be efficacious, inexpensive, safe to manufacture, and easy to administer (3). The feasibility of current IPV in developing countries is limited, because IPV is more expensive than OPV and is administered through injections only. ...
The aim of current study was to develop a dried inactivated polio vaccine (IPV) formulation with minimal loss during the drying process and improved stability when compared with the conventional liquid IPV.
Extensive excipient screening was combined with the use of a Design of Experiment (DoE) approach in order to achieve optimal results with high probability.
Although it was shown earlier that the lyophilization of a trivalent IPV while conserving its antigenicity is challenging, we were able to develop a formulation that showed minimal loss of potency during drying and subsequent storage at higher temperatures.
This study showed the potential of a highly stable and safe lyophilized polio vaccine, which might be used in developing countries without the need of a cold-chain.
Viruses are notorious for causing a significant array of infectious diseases, rendering them a prominent contributor to global morbidity and mortality rates. Throughout history, various regions have experienced outbreaks, epidemics, and pandemics, resulting in significant mortality rates. The Influenza virus gave rise to highly fatal outbreaks that disseminated on a global scale, subsequently resulting in a pandemic during the initial decades of the 20th century. This catastrophic event led to >75 million fatalities, accompanied by a substantial incidence of illnesses. In addition to the development of efficacious treatments for viral diseases, it is imperative to establish and implement various preventive measures to mitigate the transmission of diseases within both local and global populations. Furthermore, it is critical to implement proven conventional and contemporary strategies for managing viral infections, alongside bolstered surveillance systems. Viruses employ diverse modes of transmission, encompassing respiratory, oral-fecal, blood-borne, and vector-borne pathways. Consequently, effective measures to mitigate viral dissemination must be tailored to address each distinct route of transmission. This review discusses the existing strategies employed to mitigate the transmission and containment of viral outbreaks, as well as the dissemination of the disease within a sizable population, intending to reduce their detrimental and fatal impacts on a community.
Viruses are notorious for causing a significant array of infectious diseases, rendering them a prominent contributor to global morbidity and mortality rates. Throughout history, various regions have experienced outbreaks, epidemics, and pandemics, resulting in significant mortality rates. The Influenza virus gave rise to highly fatal outbreaks that disseminated on a global scale, subsequently resulting in a pandemic during the initial decades of the 20 th century. This catastrophic event led to >75 million fatalities, accompanied by a substantial incidence of illnesses. In addition to the development of efficacious treatments for viral diseases, it is imperative to establish and implement various preventive measures to mitigate the transmission of diseases within both local and global populations. Furthermore, it is critical to implement proven conventional and contemporary strategies for managing viral infections, alongside bolstered surveillance systems. Viruses employ diverse modes of transmission, encompassing respiratory, oral-fecal, blood-borne, and vector-borne pathways. Consequently, effective measures to mitigate viral dissemination must be tailored to address each distinct route of transmission. This review discusses the existing strategies employed to mitigate the transmission and containment of viral outbreaks, as well as the dissemination of the disease within a sizable population, intending to reduce their detrimental and fatal impacts on a community.
The purpose of this study was to determine if a methanolic extract of the Pulsatilla patens (L.) Mill. can inhibit the progression of cancer through the modulation of cancer-related metabolic signaling
pathways. We analyzed a panel of 13 inducible luciferase reporter gene vectors which expression is driven by enhancer elements that bind to specific transcription factors for the evaluation of the
activity of cancer signaling pathways. The root extract of P. patens exhibited strong inhibition of several signaling pathways in HeLa cells, a cervical cancer cell line, and was found to be the most potent in inhibiting the activation of Stat3, Smad, AP-1, NF-κB, MYC, Ets, Wnt and Hdghog, at a concentration of 40 μg/mL. The methanolic extracts of P. patens enhanced apoptotic death, deregulated cellular proliferation, differentiation, and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. This is the first study to report the influence of Pulsatilla species on cancer signaling pathways. Further, our detailed phytochemical analysis of the methanolic extracts of the P. patens allowed to deduce that compounds, which strongly suppressed the growth and proliferation of HeLa cancer cells were mainly triterpenoid saponins accompanied by phenolic acids.
Coronavirus disease 19 (COVID-19) continues to challenge most scientists in the search of an effective way to either prevent infection or to avoid spreading of the disease. As result of global efforts some advances have been reached and we are more prepared today than we were at the beginning of the pandemic, however not enough to stop the transmission, and many questions remain unanswered. The possibility of reinfection of recovered individuals, the duration of the immunity, the impact of SARS-CoV-2 mutations in the spreading of the disease as well as the degree of protection that a potential vaccine could have are some of the issues under debate. A number of vaccines are under development using different platforms and clinical trials are ongoing in different countries, but even if they are licensed it will need time until reach a definite conclusion about their real safety and efficacy. Herein we discuss the different strategies used in the development of COVID-19 vaccines, the questions underlying the type of immune response they may elicit, the consequences that new mutations may have in the generation of sub-strains of SARS-CoV-2 and their impact and challenges for the efficacy of potential vaccines in a scenario postpandemic.
Résumé L’Initiative Mondiale pour l’Éradication de la Poliomyélite (IMEP), lancée en 1988, repose sur 2 stratégies : la vaccination de masse par le vaccin polio oral (VPO) et la surveillance des cas de paralysie flasque aiguë (PFA). L’incidence de la maladie a été réduite de 99 %, mais l’éradication, initialement prévue pour l’an 2000, n’est toujours pas atteinte en 2010 et 4 pays restent endémiques (Inde, Pakistan, Afghanistan et Nigeria). Les obstacles à l’éradication sont : la difficulté d’atteindre tous les enfants à vacciner, notamment dans les zones d’insécurité ; les imperfections du VPO, d’efficacité irrégulière et génétiquement instable ; les limites de la surveillance, qui ne détecte que les formes paralytiques d’une maladie qui reste le plus souvent asymptomatique. Les reports successifs de l’échéance finale, qui ont considérablement alourdi le coût de l’IMEP, suscitent un débat quant à la réelle faisabilité de l’éradication et à la justification de continuer à financer, dans un contexte économique mondial difficile, une initiative sans impact significatif sur les indicateurs des Objectifs du Millenium pour le Développement (OMD).
The word “polio ” has been used to describe both a disease and the disease agent. Among current methods to measure the importance of or interest in a topic is to run a general web search for the term and to search the scientific literature in PubMed. A Google web search of the word “polio” in Aug 2010 yielded 31,100,000 hits, while a search in PubMed yielded 22,000 articles and 826 review articles. This review will concentrate on those aspects of the epidemiology of polio as it relates to disease eradication and the sustainability of this effort. The terms “polio” and “poliomyelitis ” will be used when describing the disease and “poliovirus” and related terms such as “polio vaccine ” will be used to describe the agent that causes the disease.
Oral vaccines offer significant advantages as the polio eradication campaign has demonstrated, over delivery via needle and syringe. Additionally, mucosal immunity generated by oral vaccines, along with systemic immunity, can provide an important means of controlling infections that are caused by pathogens that infect the gut mucosa. There are a number of approaches being evaluated to deliver vaccines orally and efforts are also being devoted to understand the mechanism of determining the generation of oral immunity and overcoming oral tolerance.
The history of polio vaccines and their use illustrates the concept of evolution of vaccines driven by changing epidemiological and socioeconomic conditions. The development of two vaccines against poliomyelitis-inactivated Salk vaccine (IPV) and live oral Sabin vaccine (OPV)-is among the most consequential achievements of prophylactic medicine of the past century. Each with their own strengths and weaknesses, they were used over the past 50 years in different settings and different regimens and combinations. This resulted in virtual elimination of the disease in almost the entire world with the exception of a few countries. Continuation of the eradication campaign coordinated by WHO may soon result in complete cessation of wild poliovirus transmission, and poliovirus may join smallpox virus in the club of extinct pathogens. However, unlike smallpox vaccination that was stopped after the interruption of virus circulation, vaccination against poliomyelitis will have to continue into the foreseeable future, due to significant differences in the nature and epidemiology of the viruses. This chapter reviews the reasons for the need to maintain high population immunity against polioviruses, makes the case for developing a new generation of polio vaccines, and discusses their desirable properties as well as new vaccine technologies that could be used to create polio vaccines for the post-eradication environment.
Background:
An inactivated poliovirus vaccine (IPV) based on attenuated poliovirus strains (Sabin-1, -2 and -3) was developed for technology transfer to manufacturers in low- and middle-income countries in the context of the global polio eradication initiative.
Method:
Safety and immunogenicity of Sabin-IPV (sIPV) was evaluated in a double-blind, randomized, controlled, dose-escalation trial in the target population. Healthy infants (n=20/group) aged 56-63 days, received a primary series of three intramuscular injections with low-, middle- or high-dose sIPV with or without aluminum hydroxide or with the conventional IPV based on wild poliovirus strains (wIPV). Virus-neutralizing titers against both Sabin and wild poliovirus strains were determined before and 28 days after three vaccinations.
Results:
The incidence of local and systemic reactions was comparable with the wIPV. Seroconversion rates after three vaccinations were 100% for type 2 and type 3 polioviruses (both Sabin and wild strains) and 95-100% for type 1 polioviruses. Median titers were high in all groups. Titers were well above the log2(titer) correlated with protection (=3) for all groups. Median titers for Sabin-2 were 9.3 (range 6.8-11.5) in the low-dose sIPV group, 9.2 (range 6.8-10.2) in the low-dose adjuvanted sIPV group and 9.8 (range 5.5-15.0) in the wIPV group, Median titers against MEF-1 (wild poliovirus type 2) were 8.2 (range 4.8-10.8) in the low-dose sIPV group, 7.3 (range 4.5-10.2) in the low-dose adjuvanted Sabin-IPV group and 10.3 (range 8.5-17.0) in the wIPV group. For all poliovirus types the median titers increased with increasing dose levels.
Conclusion:
sIPV and sIPV adjuvanted with aluminum hydroxide were immunogenic and safe at all dose levels, and comparable with the wIPV. EudraCTnr: 2011-003792-11, NCT01709071.
The number of cases of paralytic poliomyelitis has declined in Nigeria since the introduction of newly licensed monovalent oral poliovirus vaccines and new techniques of vaccine delivery. Understanding the relative contribution of these vaccines and the improved coverage to the decline in incident cases is essential for future planning.
We estimated the field efficacies of monovalent type 1 oral poliovirus vaccine and trivalent oral poliovirus vaccine, using the reported number of doses received by people with poliomyelitis and by matched controls as identified in Nigeria's national surveillance database, in which 27,379 cases of acute flaccid paralysis were recorded between 2001 and 2007. Our estimates of vaccine coverage and vaccine-induced immunity were based on the number of doses received by children listed in the database who had paralysis that was not caused by poliovirus.
The estimated efficacies per dose of monovalent type 1 oral poliovirus vaccine and trivalent oral poliovirus vaccine against type 1 paralytic poliomyelitis were 67% (95% confidence interval [CI], 39 to 82) and 16% (95% CI, 10 to 21), respectively, and the estimated efficacy per dose of trivalent oral poliovirus vaccine against type 3 paralytic poliomyelitis was 18% (95% CI, 9 to 26). In the northwestern region of Nigeria, which reported the majority of cases during the study period, coverage with at least one dose of vaccine increased from 59 to 78%. Between 2005 and 2007, vaccine-induced immunity levels among children under the age of 5 years more than doubled, to 56%.
The higher efficacy of monovalent type 1 oral poliovirus vaccine (four times as effective as trivalent oral poliovirus vaccine) and the moderate gains in coverage dramatically increased vaccine-induced immunity against serotype 1 in northern Nigeria. Further increases in coverage in Nigerian states with infected populations are required to achieve the levels of vaccine-induced immunity associated with the sustained elimination achieved in other parts of the country.
In 1988, the World Health Assembly resolved to eradicate poliomyelitis. Although substantial progress toward this goal has been made, eradication remains elusive. In 2004, the World Health Organization called for the development of a potentially more immunogenic monovalent type 1 oral poliovirus vaccine.
We conducted a trial in Egypt to compare the immunogenicity of a newly licensed monovalent type 1 oral poliovirus vaccine with that of a trivalent oral poliovirus vaccine. Subjects were randomly assigned to receive one dose of monovalent type 1 oral poliovirus vaccine or trivalent oral poliovirus vaccine at birth. Thirty days after birth, a single challenge dose of monovalent type 1 oral poliovirus vaccine was administered in all subjects. Shedding of serotype 1 poliovirus was assessed through day 60.
A total of 530 subjects were enrolled, and 421 fulfilled the study requirements. Thirty days after the study vaccines were administered, the rate of seroconversion to type 1 poliovirus was 55.4% in the monovalent-vaccine group, as compared with 32.1% in the trivalent-vaccine group (P<0.001). Among those with a high reciprocal titer of maternally derived antibodies against type 1 poliovirus (>64), 46.0% of the subjects in the monovalent-vaccine group underwent seroconversion, as compared with 21.3% in the trivalent-vaccine group (P<0.001). Seven days after administration of the challenge dose of monovalent type 1 vaccine, a significantly lower proportion of subjects in the monovalent-vaccine group than in the trivalent-vaccine group excreted type 1 poliovirus (25.9% vs. 41.5%, P=0.001). None of the serious adverse events reported were attributed to the trial interventions.
When given at birth, monovalent type 1 oral poliovirus vaccine is superior to trivalent oral poliovirus vaccine in inducing humoral antibodies against type 1 poliovirus, overcoming high preexisting levels of maternally derived antibodies, and increasing the resistance to excretion of type 1 poliovirus after administration of a challenge dose. (Current Controlled Trials number, ISRCTN76316509.)
An outbreak of paralytic poliomyelitis occurred in the Dominican Republic (13 confirmed cases) and Haiti (8 confirmed cases,
including 2 fatal cases) during 2000–2001. All but one of the patients were either unvaccinated or incompletely vaccinated
children, and cases occurred in communities with very low (7 to 40%) rates of coverage with oral poliovirus vaccine (OPV).
The outbreak was associated with the circulation of a derivative of the type 1 OPV strain, probably originating from a single
OPV dose given in 1998–1999. The vaccine-derived poliovirus associated with the outbreak had biological properties indistinguishable
from those of wild poliovirus.
Full-length poliovirus complementary DNA (cDNA) was synthesized by assembling oligonucleotides of plus and minus strand polarity. The synthetic poliovirus cDNA was transcribed by RNA polymerase into viral RNA, which translated and replicated in a cell-free extract, resulting in the de novo synthesis of infectious poliovirus. Experiments in tissue culture using neutralizing antibodies and CD155 receptor-specific antibodies and neurovirulence tests in CD155 transgenic mice confirmed that the synthetic virus had biochemical and pathogenic characteristics of poliovirus. Our results show that it is possible to synthesize an infectious agent by in vitro chemical-biochemical means solely by following instructions from a written sequence.
Oral transmission of poliovirus is restricted to humans and certain primate species. The expression of the human poliovirus
receptor (CD155) within gastrointestinal-associated lymphoid tissues from species that are susceptible (human) or resistant
(rhesus macaque and CD155 transgenic [Tg] mice) to oral poliovirus infection was examined. Sensitivity to oral infection correlated with CD155 expression
not only in the intestinal epithelium, including the follicle-associated epithelium (FAE) and microfold (M) cells of Peyer’s
patches, but also in germinal centers within the Peyer’s patches. CD155 expression in rhesus macaques was reduced in FAE and,
significantly, absent in germinal centers. In CD155 Tg mice, CD155 expression was barely observable in the intestinal epithelium, absent in germinal centers, but prominent in
the tunica muscularis. This suggests that productive poliovirus infection of the gut is dependent on the expression of CD155
within the FAE, including the M cells, and on cells within Peyer’s patches, most likely within germinal centers
The global eradication of poliomyelitis will require substantial changes in immunization practices. One of the proposed scenarios
includes cessation of vaccination with live oral poliovirus vaccine (OPV) and the creation of an OPV stockpile for emergency
response in case of the reintroduction of poliovirus into circulation. We describe here a retrospective analysis of the cessation
of OPV usage in a region of the Byelorussian Republic of the former Soviet Union in 1963 to 1966. During this period, a widespread
circulation and evolution of independent lineages of vaccine-derived polioviruses took place in the region. Some of these
lineages appeared to originate from OPV given to 40 children in the community during this period of essentially no vaccinations.
The data demonstrate very high risks associated with both the local cessation of OPV vaccination and the proposed use of OPV
to control a possible reemergence of poliovirus in the postvaccination period. The high transmissibility of OPV-derived viruses
in nonimmune population, documented here, and the known existence of long-term OPV excretors should be also considered in
assessing risks of the synchronized global cessation of OPV usage.
Two types of vaccine-derived polioviruses have been recently designated to emphasize the different origins of the evolved viruses: circulating vaccine-derived polioviruses (cVDPV) associated with outbreaks of paralytic disease and strains isolated from chronically infected immunodeficient individuals (iVDPV). We describe here a type 3 VDPV (PV3/EST/02/E252; later E252) isolated from sewage collected in Tallinn, Estonia, in October 2002. Due to aberrant properties in subtyping, the virus was subjected to detailed characterization. Partial genomic sequencing suggested that the closest relative was the oral vaccine strain PV3/Sabin, but the two virus strains shared only 86.7% of the 900 nucleotides (nt) coding for the capsid protein VP1. Phylogenetic analysis of the nearly complete genome [nt 19 to poly(A)] revealed multiple nucleotide substitutions throughout the genome and a possible Sabin 3/Sabin 1-recombination junction site in the 2C coding region. A calculation based on the estimated mutation frequency of the P1 region of polioviruses suggested that the E252 virus might have replicated in one or more individuals for approximately 10 years. No persons chronically excreting poliovirus are known in Estonia. Amino acid substitutions were seen in all known antigenic sites, which was consistent with the observed aberrant antigenic properties of the virus demonstrated by both monoclonal antibodies and human sera from vaccinated children. In spite of the apparent transmission potential, no evidence was obtained for circulation of the virus in the Estonian population.
The last case of poliomyelitis in the United States due to indigenously acquired wild poliovirus occurred in 1979; however, as a consequence of oral poliovirus vaccine (OPV) use that began in 1961, an average of 9 cases of vaccine-associated paralytic poliomyelitis (VAPP) were confirmed each year from 1961 through 1989. To reduce the VAPP burden, national vaccination policy changed in 1997 from reliance on OPV to options for a sequential schedule of inactivated poliovirus vaccine (IPV) followed by OPV. In 2000, an exclusive IPV schedule was adopted.
To review the epidemiology of paralytic poliomyelitis and document the association between the vaccine schedule changes and VAPP in the United States.
Review of national surveillance data from 1990 through 2003 for cases of confirmed paralytic poliomyelitis.
Number of confirmed paralytic poliomyelitis cases, including VAPP, and ratio of VAPP cases to number of doses of OPV distributed that occurred before, during, and after implementation of policy changes.
From 1990 through 1999, 61 cases of paralytic poliomyelitis were reported; 59 (97%) of these were VAPP (1 case per 2.9 million OPV doses distributed), 1 case was imported, and 1 case was indeterminate. Thirteen cases occurred during the 1997-1999 transitional policy period and were associated with the all-OPV schedule; none occurred with the IPV-OPV schedule. No cases occurred after the United States implemented the all-IPV policy in 2000. The last imported poliomyelitis case occurred in 1993 and the last case of VAPP occurred in 1999.
The change in polio vaccination policy from OPV to exclusive use of IPV was successfully implemented; this change led to the elimination of VAPP in the United States.
The feasibility of global polio eradication is being questioned as a result of continued transmission in a few localities that act as sources for outbreaks elsewhere. Perhaps the greatest challenge is in India, where transmission has persisted in Uttar Pradesh and Bihar despite high coverage with multiple doses of vaccine. We estimate key parameters governing the seasonal epidemics in these areas and show that high population density and poor sanitation cause persistence by not only facilitating transmission of poliovirus but also severely compromising the efficacy of the trivalent vaccine. We analyze strategies to counteract this and show that switching to monovalent vaccine may finally interrupt virus transmission.
Vaccine-derived polioviruses (VDPVs) have caused poliomyelitis outbreaks in communities with sub-optimal vaccination. Israeli environmental surveillance of sewage from populations with high (>95%) documented vaccine coverage of confirmed efficacy identified two separate evolutionary clusters of VDPVs: Group 1 (1998-2005, one system, population 1.6x10(6)) and Group 2 (2006, 2 systems, populations 0.7x10(6) and 5x10(4)).
Molecular analyses support evolution of nine Group 1 VDPVs along five different lineages, starting from a common ancestral type 2 vaccine-derived Sabin-2/Sabin-1 recombinant strain, and independent evolution of three Group 2 VDPVs along one lineage starting from a different recombinant strain. The primary evidence for two independent origins was based on comparison of unique recombination fingerprints, the number and distribution of identical substitutions, and evolutionary rates. Geometric mean titers of neutralizing antibodies against Group 1 VDPVs were significantly lower than against vaccine strains in all age-group cohorts tested. All individuals had neutralizing titers >1:8 against these VDPVs except 7% of the 20-50 year cohort. Group 1 VDPVs were highly neurovirulent in a transgenic mouse model. Intermediate levels of protective immunity against Group 2 VDPVs correlated with fewer (5.0+1.0) amino acid substitutions in neutralizing antigenic sites than in Group 1 VDPV's (12.1+/-1.5).
VDPVs that revert from live oral attenuated vaccines and reacquire characteristics of wild-type polioviruses not only threaten populations with poor immune coverage, but are also a potential source for re-introduction of poliomyelitis into highly immune populations through older individuals with waning immunity. The presence of two independently evolved groups of VDPVs in Israel and the growing number of reports of environmental VDPV elsewhere make it imperative to determine the global frequency of environmental VDPV. Our study underscores the importance of the environmental surveillance and the need to reconsider the global strategies for polio eradication and the proposed cessation of vaccination.
In 1988, the World Health Assembly launched the Global Polio Eradication Initiative, which aimed to use large-scale vaccination with the oral vaccine to eradicate polio worldwide by the year 2000. Although important progress has been made, polio remains endemic in several countries. Also, the current control measures will likely be inadequate to deal with problems that may arise in the postpolio era. A panel convoked by the National Research Council concluded that the use of antiviral drugs may be essential in the polio eradication strategy. We here report on a comparative study of the antipoliovirus activity of a selection of molecules that have previously been reported to be inhibitors of picornavirus replication and discuss their potential use, alone or in combination, for the treatment or prophylaxis of poliovirus infection.
We assessed the costs, risks, and benefits of possible future major policy decisions on vaccination, surveillance, response plans, and containment following global eradication of wild polioviruses.
We developed a decision analytic model to estimate the incremental cost-effectiveness ratios and net benefits of risk management options for polio for the 20-year period and stratified the world according to income level to capture important variability between nations.
For low-, lower-middle-, and upper-middle-income groups currently using oral poliovirus vaccine (OPV), we found that after successful eradication of wild polioviruses, OPV cessation would save both costs and lives when compared with continued use of OPV without supplemental immunization activities. We found cost-effectiveness ratios for switching from OPV to inactivated poliovirus vaccine to be higher (i.e., less desirable) than other health investment opportunities, depending on the actual inactivated poliovirus vaccine costs and assumptions about whether supplemental immunization activities with OPV would continue.
Eradication promises billions of dollars of net benefits, although global health policy leaders face difficult choices about future policies. Until successful eradication and coordination of posteradication policies, health authorities should continue routine polio vaccination and supplemental immunization activities.
PIP
The emergence of a debate in the US regarding poliomyelitis immunization practices makes it important to examine unresolved issues about the epidemiology of this disease. The literature suggests that poliomyelitis initially appears as a disease of preschool children, but then there is a trend toward increasing age of cases. Age differences in the case: infection ratio do not appear to have a consistent, predictable impact on overall incidence. The appearance of epidemic poliomyelitis is assumed to have resulted from a reduction in levels of maternal antibodies as booster reinfections became less common, a reduction in the frequency of antibody levels sufficient to produce cross-protection between virus types, and an increase in the average age of primary infections. The relative importance of virus virulence and of elevated infection rate in the production of epidemics remains unknown. The use of poliovirus vaccine in the US has reduced paralytic disease from an annual incidence of about 10,000 cases to 10 cases. The eradication of poliomyelitis in spite of the fact that no more than 90% of US children have been reached indicates that either vaccine virus has spread to the unimmunized or a herd immunity effect is operating and the resultant disappearance of wild poliovirus prevents exposure of the unimmunized. The unexpected eradication of natural poliomyelitis in the US has raised the problem of vaccine-associated disease when oral vaccine is used. Since oral poliovirus vaccine appears to have provided protection through herd immunity, any change in immunization practices that might increase the exposure of susceptibles should be undertaken with great caution. Evidence of repeated importations of wild poliovirus emphasizes this concern. If inactivated vaccine is seriously considered for primary immunization, it should be followed by reimmunization with oral vaccine.
In 1988, the World Health Assembly resolved to eradicate poliomyelitis worldwide. The live, attenuated oral poliovirus vaccine (OPV) has many advantages favoring its use in polio eradication: it is administered easily by mouth; confers intestinal immunity, making recent OPV recipients resistant to infection by wild polioviruses (WPVs); provides long-term protection against paralytic disease through durable humoral immunity; and is inexpensive. Despite its many advantages, OPV use carries the risk for occurrence of rare cases of vaccine-associated paralytic poliomyelitis among immunologically normal OPV recipients and their contacts and the additional risk for emergence of vaccine-derived polioviruses (VDPVs). Because of these risks, OPV use will be discontinued worldwide once the goal of eradicating all WPV transmission is achieved. VDPVs can cause polio outbreaks in areas with low OPV coverage and can replicate for years in immunodeficient persons; therefore, strategies to strengthen global polio immunization and surveillance are needed to limit emergence of VDPVs. This report updates previous surveillance summaries and describes VDPVs detected worldwide during July 2009--March 2011 and reported as of June 20, 2011. Three new outbreaks of circulating VDPVs (cVDPVs), ranging in size from six to 16 cases, were identified in Afghanistan, Ethiopia, and India; three previously identified outbreaks in Nigeria, Democratic Republic of Congo (DRC), and Somalia continued through late 2010 or into 2011 and resulted in 355, 37, and 13 total cases, respectively; two countries experienced importations of cVDPVs from Nigeria; nine newly identified paralyzed immunodeficient persons in seven middle-income and developing countries were found to excrete VDPVs; and VDPVs were found among persons and environmental samples in 15 countries. With the use of alternate OPV formulations since 2005 and with enhanced poliovirus surveillance sensitivity and laboratory screening, the number of identified cVDPV outbreaks per year has increased over time . To prevent VDPV emergence and spread, all countries should maintain high poliovirus vaccination coverage against all three poliovirus serotypes. Sensitive poliovirus surveillance to detect VDPVs will continue to increase in importance.
The purpose of the poliomyelitis vaccine evaluation program in the field trial of 1954 was to seek a measure of the prophylactic effect of the preparations of vaccine to be used, the only assumptions 'being that the experimental background was sound and that the vaccine was to be antigenic and noninfectious. The undertaking meant the acceptance of a public and scientific trust to provide, so far as possible, an objective analysis and unprejudiced appraisal of data obtained from numerous study areas. It must be fully realized that the evaluation program was not a tightly knit operation carried on by a single group of investigators. Rather, it was a widespread series of investigations that the vaccine evaluation center at the University of Michigan sought to integrate by obtaining uniform acceptance of instructions and procedures and, thus, to maintain uniformity of understanding and performance and completeness and accuracy of investigation and report.
It has often been observed by clinicians that certain patients with paralytic poliomyelitis give a history of severe exertion immediately preceding the onset of paralysis. The inference has been that perhaps undue exertion in some way precipitated the paralysis. Trauma preceding onset has also been mentioned as a possible predisposing cause. Recently it has been postulated on both clinical and theoretic grounds that physical activity at a crucial time might be one of the factors which determines the degree of spread of virus in the central nervous system and therefore the severity of the disease.1 Levinson, Milzer and Lewin studied experimentally the effects of fatigue, chilling and mechanical trauma during the incubation period on the resistance of rhesus monkeys to poliomyelitis.2 They found that the incidence and severity of paralysis was greater in monkeys subjected to exhausting exercise or chilling than in control animals; no correlation was demonstrated
The incubation period in human poliomyelitis is not subject to exact analysis because of gaps in present knowledge concerning the mode of spread of the disease. Thus it is unknown what constitutes adequate exposure to virus in order to produce human infection, as well as what form (or forms) exposure may take. Furthermore, not only is there difficulty in knowing at what point the incubation period begins but there is some confusion about measuring its termination, i, e., a lack of agreement as to which shall be regarded as the first day of the clinical disease. It will be our purpose in this paper to review some of the existing data concerned with the incubation period in human poliomyelitis and to consider also its significance in terms of the pathogenesis of the disease.
The incubation period in poliomyelitis is generally given in textbooks as ranging from six to twelve days,
Twenty years of global polio eradication efforts may soon eliminate the transmission of wild-type poliovirus. However, new
information that has been learned about poliovirus, as well as the political realities of a modern world, demand that universal
immunity against poliomyelitis be maintained, even after wild-type poliovirus is eradicated. Although 2 excellent vaccines
have proven to be highly effective in the past, neither the live-attenuated vaccine nor the currently used inactivated vaccine
are optimal for use in the posteradication era. Therefore, concerted efforts are urgently needed to develop a new generation
of vaccine that is risk-free and affordable and can be produced on a global scale. Here, we discuss the desired properties
of a vaccine and methods to create a new polio vaccine.
We investigated an immunodeficient child in whom chronic progressive poliomyelitis developed after she had received live oral poliovirus vaccine. Poliovirus, Type II, was isolated from throat and stool during life and from several sites within the brain at autopsy. The brain isolate was classified as vaccine-like on the basis of temperature sensitivity and antigenic markers. However, in the monkey neurovirulence test, the brain isolate produced moderately severe lesions throughout the spinal cord and brainstem and appeared nonvaccine-like. Thus, the brain isolate demonstrated a dissociation between the antigenic and neurovirulence markers. Our observations suggest that, under unusual circumstances, such as immunodeficiency, attenuated poliovirus can produce a chronic progressive neurologic disease. This case also emphasizes the need to diagnose immunodeficiency as early as possible, so that live-virus vaccines will not be administered.
A transgenic mouse model was used to address an unsolved question in the pathogenesis of poliomyelitis: how poliovirus invades
the central nervous system (CNS). LDS50 values for intramuscular and intracerebral inoculation of poliovirus in transgenic mice expressing poliovirus receptors (TgPVR
mice) were similar. After intramuscular inoculation with oliovirus, paralysis was observed first in the inoculated limb.
In contrast, localization of initial paralysis to the inoculated limb was not observed in normal mice inoculated intramuscularly
with the mouse-adapted P2/Lansing poliovirus strain. After intramuscular inoculation, infectious poliovirus was first detected
in the inferior segment of the spinal cord, then in the superior spinal cord and the brain. Sciatic nerve transection blocked
poliovirus spread to the spinal cord after inoculation into the hindlimb footpad of TgPVR mice. These results demonstrate
that in TgPVR mice, poliovirus spreads from muscle to the CNS through nerve pathways and that expression of the poliovirus
receptor plays an important role in viral spread by this route.
Poliomyelitis caused by polioviruses has already been eradicated from industrialized countries of North America, Europe, Asia and Oceania, but the procedures by which this eradication was achieved are not adequate for the poor tropical and subtropical countries. The major challenge now is first to eliminate it rapidly from Asia and Africa where an estimated 250,000 cases and 25,000 deaths currently occur annually. The great progress toward eradication of "wild" polioviruses from poor tropical and subtropical countries in Latin America was achieved not by the procedures still recommended by the WHO Expanded Program on Immunization (EPI) but by the independently organized annual, national days of antipolio vaccination - all based on the use of large armies of well-trained non-professional, community volunteers - first used in Cuba (1962), Brazil (1980), Nicaragua (1981), Dominican Republic (1983), Paraguay (1985), and Mexico (1986). This novel approach, described in some detail in this communication, is recommended for the rapid elimination of wild polioviruses from Asia and Africa, and for ultimate global eradication with the help of a special cadre within the EPI of WHO. The extensive use by the Pan American Health Organization (PAHO) of highly sophisticated regional virus laboratories has led to the recognition that, in areas from which poliomyelitis caused by polioviruses has been largely eliminated, there are thousands of cases of acute flaccid paralysis, previously clinically diagnosed as "probable poliomyelitis", that have no viral etiology, a phenomenon previously reported by Dr. Manuel Ramos Alvarez in Mexico City in 1967.
In a randomized, controlled trial carried out from November 1980 to July 1983 involving 1,114 infants in Baltimore City and in Baltimore and Prince George's counties, Maryland, the serologic response to three doses of two enhanced-potency inactivated polio vaccines was compared with the response to three doses of oral polio vaccine. The mean ages at vaccination were 2.2, 4.7, and 19.9 months, respectively, for the three doses. Seroconversion after the first dose varied from 35% to 84%, and it was higher after oral polio vaccine than after either of the enhanced-potency inactivated polio vaccines for polioviruses types 2 and 3. Approximately two and one-half and 16 months after the second dose, almost all inactivated polio vaccine recipients had antibodies against all three virus types (98-100%). Fewer oral polio vaccine recipients had detectable antibodies to type 1 (89-92%) and to type 3 (96%). After three doses of vaccine, all children had antibodies against types 2 and 3. Approximately 1% of the inactivated polio vaccine recipients and 3% of the oral polio vaccine recipients lacked antibody to type 1. One or two doses of oral polio vaccine stimulated higher reciprocal geometric mean antibody titers against type 2 poliovirus than did the inactivated polio vaccine. For the other two types, the results were mixed. The third dose of inactivated polio vaccine produced significant increases in the reciprocal geometric mean titers against each of the three poliovirus types and resulted in significantly higher reciprocal geometric mean titers after three doses of vaccine for recipients of inactivated polio vaccine than for recipients of oral polio vaccine.
Oral poliovirus vaccine (OPV) is like no other live virus vaccine used in humans: vaccine strains multiply extensively in the intestinal tract, are widely disseminated in the family and community, and immunize a large proportion of the unvaccinated population. During the search for optimal strains for vaccine use, motor neurons in the spinal cord of chimpanzees (and by extrapolation those of humans) were found to be much more resistant to polioviruses than those of monkeys; the reverse was true for the alimentary tract. Various biologic properties of polioviruses also varied quantitatively over a wide spectrum and were genetically distinct. The phenomenon of somewhat increased neurovirulence for monkeys, but not for chimpanzees, encountered in excreted virus was extensively studied in families, in children's homes, and finally among hundreds of thousands of susceptible children and adults in areas where only 50% of the susceptible population received OPV; these studies did not reveal evidence of danger. During the past 20 years approximately 5 million cases of paralytic poliomyelitis were probably prevented by OPV in predominantly temperate-climate countries inhabited by approximately 2 billion people. OPV has also been used less extensively and not optimally in many tropical and subtropical countries, where paralytic poliomyelitis is now known to be an important public health problem, with reduction in numbers of cases but not elimination of the disease except in some countries with better health services. Experience in Cuba during the past 21 years, in Brazil during the past 5 years, and in the Dominican Republic during the past 2 years has shown that the strategy of annual short-term vaccination of all children in the most susceptible age groups can rapidly eliminate the disease from tropical and subtropical countries.
The immunogenic efficacy of inactivated poliovirus vaccine of enhanced potency (IPV-E), containing 40, 8 and 32 D-antigen units of types 1, 2 and 3, respectively, was evaluated in tritypic seronegative infants. Eighty infants aged six to 45 weeks, with no antibody detectable at a 1 : 4 dilution, were given two doses of a quadruple vaccine containing diphtheria-pertussis-tetanus (DPT) vaccine and IPV-E at intervals of four weeks (37 infants, group 1) or eight weeks (43 infants, group 2) between doses. All infants of group 2 responded with antibody to the three types of polioviruses. In group 1, all responded to types 1 and 3 antigens but only 36 responded to type 2. Antibody titres were higher in infants immunized at eight week than at four week intervals. Thus, two doses of IPV-E, especially when given eight weeks apart, are sufficient for primary immunization against poliomyelitis. If DPT vaccine of enhanced potency is combined with IPV-E, two doses of such a quadruple vaccine may be sufficient for primary immunization against four diseases; this possibility deserves evaluation.
The incidence of natural poliomyelitis in hypogammaglobulinemics has been estimated to be similar to that in nonimmune normal
children of the same age group exposed to virulent poliovirus. Poliomyelitis that afflicts hypogammaglobulinemics after the
feeding of oral polio vaccine is characterized by an incubation period of longer than 28 days, a high rate of mortality after
a long chronic illness, abnormal lesions in the central nervous system, and no reversion of the vaccine virus to virulence.
Nearly 10% of vaccine-associated cases are in hypogammaglobulinemics, who are estimated to be 10,000 times more susceptible
to vaccine-induced poliomyelitis than normal persons. It is suggested that only inactivated poliovaccine be given to hypogammaglobulinemics,
that all suspected cases of vaccine-induced poliomyelitis be tested for γ-globulin status, and that persons be tested for
antibodies to poliovirus before treatment with immunosuppressive drugs.
Human poliovirus infection in mice was studied to determine the similarities to human poliomyelitis, the selective vulnerability of neurons to infection, the role of the immune response in age-dependent susceptibility, and possible viral persistence. Mice inoculated intracerebrally (ic) with the Lansing type 2 poliovirus developed a disease with clinical, pathological, and age-dependent features resembling human poliomyelitis. Adult mice had a shorter incubation period (50% paralysis, Day 8 vs. Day 13) and a higher incidence of paralysis (97% vs. 79%) than newborns. Only paralyzed animals had pathologic changes in the spinal cord, and these corresponded to the degree of paralysis. Fluorescent antibody staining showed that selective infection of neurons was most intense in the anterior horn motor neurons of the spinal cord. There was no extraneural virus replication and no systemic neutralizing antibody response. Cyclophosphamide immunosuppression enhanced rather than diminished disease, indicating that maturation of immune responses did not explain the relative resistance of newborns to paralysis.
Trivalent oral poliovirus vaccine (roPV) has been used in Gaza since 1967. After an initial decrease of 33% in the incidence
of the paralytic disease, no further decrease could be noted. The mean annual incidence until 1977 was 10 per 100,000 inhabitants.
Two outbreaks caused by poliovirus type 1 were registered in 1974 and 1976 with an incidence of 18 per 100,000 inhabitants.
In these outbreaks, 34% and 50% of the affected children, respectively, had receivedthree to four doses of ropy. A new vaccination
schedule was introduced in 1978, combining live and inactivated poliovirus vaccines. In the years 1978–1980, the incidence
decreased to 2.6 per 100,000 inhabitants; and during 19811982, only three cases were recorded. These results indicate that
a schedule like the one used in Gaza could serve as a model to control poliomyelitis in developing countries where ropv alone
is not successful.
Since its first mass use in 1960, oral polio vaccine ( OPV ) has largely eliminated paralytic poliomyelitis from temperate-climate and subtropical regions of the world that have good health services and a combined total population of almost 2,000 million people. The various strategies used in these countries have been highly successful even where, as in the USA, large numbers of children received no vaccine or only a single dose of OPV . During the period of 1981-1982, only 2.8 cases per 100 million total population per year were reported in the USA. The main challenge in the present era is the economically undeveloped tropical and subtropical regions with inadequate health services that are inhabited by more than half of the world population, where recent surveys for residual paralysis due to poliomyelitis have shown that the incidence of the disease has been higher than it was in the USA and other predominantly temperate-climate countries before the vaccine era. The problem in these countries is that the majority of children receive no vaccine and that the extensive year-round dissemination of virulent polioviruses requires a different strategy of vaccination from that used in the temperate-climate countries. The special point about the annual mass vaccinations with OPV for all children younger than three, four, or five years of age-which have proven highly successful in Cuba (for the past 20 years), in Brazil (during the past three years), and recently also in Mexico-is that all the children are usually vaccinated within one or two days, which quickly breaks the chain of transmission of the virulent viruses, and the annual campaigns create and maintain the maximum number of children with resistant intestinal tracts.
Routine and mass administration of oral polio vaccine (OPV) since 1961 has prevented many millions of cases of paralytic poliomyelitis. The public health value of this inexpensive and easily administered product has been extraordinary. Progress of the Global Polio Eradication Initiative has further defined the value of OPV as well as its risk through vaccine-associated paralytic poliomyelitis (VAPP) and vaccine-derived polioviruses (VDPV). Although both are rare, once wild poliovirus transmission has been interrupted by OPV, the only poliomyelitis due to poliovirus will be caused by OPV. Poliovirus will be eradicated only when OPV use is discontinued. This paradox provides a major incentive for eventually stopping polio immunization or replacing OPV, but it also introduces complexity into the process of identifying safe and scientifically sound strategies for doing so. The core post eradication immunization issues include the risk/benefits of continued OPV use, the extent of OPV replacement with IPV, possible strategies for discontinuing OPV, and the potential for development and licensure of a safe and effective replacement for OPV. Formulation of an informed post eradication immunization policy requires careful evaluation of polio epidemiology, surveillance capability, vaccine availability, laboratory containment, and the risks posed by the very tool responsible for successful interruption of wild poliovirus transmission.
SINCE 1961 when the oral poliomyelitis vaccines were first made available for general use in the United States, scattered cases of paralytic disease have occurred in association with these vaccines. Many of the cases have been clinically indistinguishable from poliomyelitis. Epidemiologically, the pattern of their occurrence has raised the possibility that some may have been caused by the vaccine.
In 1962 when the existence of this problem was first appreciated, the Surgeon General of the Public Health Service convened a special advisory committee which met on a number of occasions between August and December. The Committee reviewed in detail reported cases of paralytic disease occurring within a period of 30 days following ingestion of the oral poliomyelitis vaccines. The Committee concluded that 18 cases of paralytic poliomyelitis were "compatible with the possibility of having been induced by the vaccine." Of these, 11 followed type III vaccine and 7 followed type
This article has no abstract; the first 100 words appear below.
MANY of the general features of the distribution of poliomyelitis are reflections of the widespread dissemination of the virus as it is affected by immunity in the population resulting from previous exposure. Within this broader pattern of distribution there are further restrictions and selectivities in the occurrence of the frank disease that are indicative of the operation of other factors of susceptibility or resistance. Among the many who are exposed to the virus, the preponderant result of which is subclinical immunization, the more frequent occurrence of frank poliomyelitis under particular circumstances and in particular categories of individuals affords some indication . . .
*From the Haynes Memorial and Evans Memorial, Massachusetts Memorial Hospitals; the Department of Medicine, Boston University School of Medicine; the Department of Preventive Medicine, Harvard Medical School; and the Division of Communicable Diseases, Massachusetts Department of Public Health.
Source Information
BOSTON
†Associate professor of medicine, Boston University School of Medicine; lecturer in infectious diseases. Harvard Medical School; chief, Infectious Disease Service (Haynes Memorial), Massachusetts Memorial Hospitals.
‡Associate professor of preventive medicine and hygiene, Harvard Medical School.
§Instructor in public health practice, Harvard School of Public Health; director, Division of Communicable Diseases, Massachusetts Department of Public Health.
A study of 75 cases of poliomyelitis in pregnancy occurring in Minnesota in 1946 is presented. Analyses of the data show:
1. There is no evidence of a greater severity of the infection among pregnant women than among a comparable group of nonpregnant married women simultaneously attacked.
2. The attack rate among pregnant women is higher than among an estimated control group of nonpregnant married women.
3. The higher attack rate in pregnancy cannot be explained on the basis of greater degree of exposure to either recognized or subclinical apparent infection.
4. Of the 75 cases in pregnancy, there was a slight concentration (and especially of serious cases) in the second to fifth month.
5. There was a dominance of male fetuses among these patients, especially those attacked in the early stages of pregnancy.
6. No significant relationship could be demonstrated between the severity of the disease in those who survived and the onset of labor.
7. Among the children born of this series the rate of congenital abnormalities was not unduly high.
Studies have been carried out on the interference phenomenon with certain neurotropic viruses in experimental animals. The primary object was to investigate claims that material containing human poliomyelitis virus interferes with the progress of the infection by the MM virus in hamsters, or the Lansing virus in mice. We have failed to find evidence that the inoculation of specimens known to contain human poliomyelitis virus interferes with the progress of MM or Lansing virus infections, and we do not believe that the interference phenomenon can be used in this way as a diagnostic test. In the course of this investigation, it was found that interference occurs when hamsters are inoculated cerebrally with lymphocytic choriomeningitis virus, and, four to seven days later, with the antigenically unrelated MM virus by the peritoneal route. A significant number of such treated animals are spared from developing paralysis due to the MM virus. Evidence was also obtained that under certain circumstances the inoculation of MM virus may lessen the severity of the illness due to lymphocytic choriomeningitis virus injected several days earlier.
Immunodeficient patients whose gut is chronically infected by vaccine-derived poliovirus (VDPV) may excrete large amounts of virus for years. To investigate how poliovirus (PV) establishes chronic infections in the gut, we tested whether it is possible to establish persistent VDPV infections in human intestinal Caco-2 cells. Four type 3 VDPV mutants, representative of the viral evolution in the gut of a hypogammaglobulinemic patient over almost 2 years [J. Virol. 74 (2000) 3001], were used to infect both undifferentiated, dividing cells, and differentiated, polarized enterocytes. A VDPV mutant excreted 36 days postvaccination by the patient was lytic in both types of intestinal cell cultures, like the parental Sabin 3 (S3) strain. In contrast, three VDPVs excreted 136, 442, and 637 days postvaccination, established persistent infections both in undifferentiated cells and in enterocytes. Thus, viral determinants selected between day 36 and 136 conferred on VDPV mutants the capacity to infect intestinal cells persistently. The percentage of persistently VDPV-infected cultures was higher in enterocytes than in undifferentiated cells, implicating cellular determinants involved in the differentiation of enterocytes in persistent VDPV infections. The establishment of persistent infections in enterocytes was not due to poor replication of VDPVs in these cells, but was associated with reduced viral adsorption to the cell surface.
1,25-Dihydroxyvitamin D3 (DHVD3) coadministered with monovalent inactivated poliovirus vaccine (IPV) of all 3 serotypes significantly
enhances antipoliovirus systemic and mucosal immunity in mice. Although serum immunoglobulin G antibodies are significantly
higher in serotypes 2 and 3, and although salivary immunoglobulin A is significantly increased in serotypes 1 and 3, DHVD3
had the most dramatic effect on the level of neutralizing serum antibodies of all 3 IPV serotypes. These findings suggest
a possible use of vitamin D3 as an adjuvant for currently used and proposed new Sabin IPV s.
A type 2 vaccine-derived poliovirus (VDPV), differing from Sabin 2 at 2.5% (22/903) of VP1 nucleotide (nt) positions, was isolated from an incompletely immunized 21-month-old Nigerian child who developed acute flaccid paralysis in 2002. Sequences upstream of nt position 620 (within the 5'-untranslated region [5'-UTR]) and downstream of nt position 5840 (in the 3C(pro) region) were derived from species C enteroviruses unrelated to the oral poliovirus vaccine (OPV) strains. The two substitutions associated with the attenuated phenotype had either recombined out (A(481)-->G in the 5'-UTR) or reverted (Ile(143)-->Thr in VP1). The VDPV isolate had lost the temperature sensitive phenotype of Sabin 2 and it was antigenically distinct from the parental OPV strain, having amino acid substitutions in or near neutralizing antigenic sites 1 and 3. The date of the initiating OPV dose, calculated from the number of synonymous substitutions in the capsid region, was estimated to be approximately 16 to 18 months before onset of paralysis, a finding inconsistent with the most recent mass OPV campaign (conducted 12 days before onset of paralysis) as being the source of infection. Although no related type 2 VDPVs were detected in Nigeria or elsewhere, the VDPV was found in an area where conditions favor VDPV emergence and spread.
Vaccine policy changes and epidemiology of poliomyelitis in the United States• Reviews the history of vaccine-associated paralytic poliomyelitis in the USA, and its elimination following the switch from routine immunization with oral poliovirus vaccine (OPV) to inactivated poliovirus vaccine
- Ln Alexander
- Jf Seward
- Santibanez
- Ln Alexander
- Jf Seward
- Santibanez
- T Francis
- Ja Napier
- Rb Voight
Francis, T.; Napier, JA.; Voight, RB., et al. Final Report. Vaccine Evaluation Center, Department of
Epidemiology, University of Michigan; Ann Arbor, MI: 1957. Evaluation of the 1954 Field Trial of
Poliomyelitis Vaccine.
New strategies for the elimination of polio from India [PubMed: 17110580] 35. el-Sayed N, el-Gamal Y, Abbassy AA, et al. Monovalent type 1 oral poliovirus vaccine in newborns
- Nc Grassly
- C Fraser
- J Wenger
Grassly NC, Fraser C, Wenger J, et al. New strategies for the elimination of polio from India. Science
2006;314(5802):1150–1153. [PubMed: 17110580]
35. el-Sayed N, el-Gamal Y, Abbassy AA, et al. Monovalent type 1 oral poliovirus vaccine in newborns.
The New England journal of medicine 2008;359(16):1655–1665. [PubMed: 18923170]