These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
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This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7703",leadTitle:null,fullTitle:"Ocular Surface Diseases - Some Current Date on Tear Film Problem and Keratoconic Diagnosis",title:"Ocular Surface Diseases",subtitle:"Some Current Date on Tear Film Problem and Keratoconic Diagnosis",reviewType:"peer-reviewed",abstract:"The ocular surface refers to the cornea, conjunctiva, lacrimal glands, and lid of the eye. It is composed of the mucosa that lines the globe and palpebrae, the corneoscleral limbus, the corneal epithelium, and the tear film. This book focuses on the tear film, describing its physiology, dynamics, and role in maintaining the health of the ocular surface. It also examines keratoconus, a condition affecting both the preocular tear film and the ocular surface in which the cornea thins and bulges outward, as well as recent possibilities in molecular genetics.",isbn:"978-1-83880-960-7",printIsbn:"978-1-83880-959-1",pdfIsbn:"978-1-83880-961-4",doi:"10.5772/intechopen.77516",price:100,priceEur:109,priceUsd:129,slug:"ocular-surface-diseases-some-current-date-on-tear-film-problem-and-keratoconic-diagnosis",numberOfPages:88,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"3dcf967eb2f185930ce7fb7ae462d4e0",bookSignature:"Dorota Kopacz",publishedDate:"January 7th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/7703.jpg",numberOfDownloads:2836,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:3,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 30th 2019",dateEndSecondStepPublish:"August 30th 2019",dateEndThirdStepPublish:"October 29th 2019",dateEndFourthStepPublish:"January 17th 2020",dateEndFifthStepPublish:"March 17th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"271261",title:"Dr.",name:"Dorota",middleName:null,surname:"Kopacz",slug:"dorota-kopacz",fullName:"Dorota Kopacz",profilePictureURL:"https://mts.intechopen.com/storage/users/271261/images/system/271261.jfif",biography:"Dorota Kopacz MD, Ph.D., is professionally connected with the Department of Ophthalmology, Medical University of Warsaw, Poland, where she is a tutor for medical, dentistry, and rescue students; a tutor for doctors during specialization in general practice, diabetology, rheumatology, and ophthalmology; and a thesis supervisor for bachelor’s degrees. She is also a consulting ophthalmologist at Infant Jesus Teaching Hospital, Warsaw, Poland. Protector for doctors during specialization in ophthalmology. Dr. Kopacz is a member of the Polish Society of Ophthalmology, European Society of Cataract and Refractive Surgery, and Cornea Society. Her clinical experience includes diagnostic procedures and non-invasive ophthalmological treatment (especially of the anterior eye segment and ocular surface), cataract surgery, secondary intraocular lens implantations, glaucoma, and ocular surface problems. She is author/coauthor of more than 160 publications, book chapters, congress papers, and posters. She is also a reviewer for local and international ophthalmological journals.",institutionString:"Medical University of Warsaw",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"191",title:"Ophthalmology",slug:"medicine-ophthalmology"}],chapters:[{id:"73710",title:"Tear Film – Physiology and Disturbances in Various Diseases and Disorders",doi:"10.5772/intechopen.94142",slug:"tear-film-physiology-and-disturbances-in-various-diseases-and-disorders",totalDownloads:787,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The tear film is a thin fluid layer covering the ocular surface. It is responsible for ocular surface comfort, mechanical, environmental and immune protection, epithelial health and it forms smooth refractive surface for vision. The traditional description of the tear film divides it into three layers: lipid, aqueous and mucin. The role of each layer depends on the composition of it. Tear production, evaporation, absorption and drainage concur to dynamic balance of the tear film and leads to its integrity and stability. Nonetheless, this stability can be disturb in tear film layers deficiencies, defective spreading of the tear film, in some general diseases and during application of some general and/or topical medications. Dry eye disease is the result of it. In this review not only physiology of the tear film is presented. Moreover, we would like to discuss the influence of various diseases and conditions on the tear film and contrarily, spotlight tear film disorders as a manifestation of those diseases.",signatures:"Dorota Kopacz, Łucja Niezgoda, Ewa Fudalej, Anna Nowak and Piotr Maciejewicz",downloadPdfUrl:"/chapter/pdf-download/73710",previewPdfUrl:"/chapter/pdf-preview/73710",authors:[{id:"271261",title:"Dr.",name:"Dorota",surname:"Kopacz",slug:"dorota-kopacz",fullName:"Dorota Kopacz"}],corrections:null},{id:"70349",title:"Biofilm Theory for Lid Margin and Dry Eye Disease",doi:"10.5772/intechopen.89969",slug:"biofilm-theory-for-lid-margin-and-dry-eye-disease",totalDownloads:434,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Blepharitis and dry eye disease have long been viewed as two distinct diseases with overlapping presentations and separate etiologies. Evaporative dry eye, although frequently associated with aqueous deficiency, is also considered a separate entity. We propose viewing dry eye, both evaporative and insufficiency, as the natural sequelae of chronic blepharitis induced by biofilm. We suggest describing this one chronic disease as dry eye blepharitis syndrome (DEBS). The disease process begins when normal flora bacteria colonize the lid margin beginning shortly after birth. This colonization accompanies the development of a biofilm on the lid margin. As years pass, the biofilm matures, and the increased bacterial population initiates the production of inflammatory virulence factors, such as exotoxins, cytolytic toxins, and super-antigens, which persist on the lid margin for the rest of the patient’s life. These virulence factors cause early follicular inflammation and later, meibomian gland dysfunction followed by aqueous insufficiency, and finally, after many decades, loss of the dense collagen in the tarsal plate. We proposed four stages of DEBS, which correlate with the clinical manifestations of folliculitis (anterior blepharitis), meibomitis (meibomian gland dysfunction), lacrimalitis (aqueous deficiency), and lid structure damage evidenced by increased lid laxity resulting in entropion, ectropion, and floppy eyelid syndrome.",signatures:"Maria Vincent, Jose Quintero, Henry D. Perry and James M. Rynerson",downloadPdfUrl:"/chapter/pdf-download/70349",previewPdfUrl:"/chapter/pdf-preview/70349",authors:[{id:"307501",title:"Dr.",name:"Henry",surname:"Perry",slug:"henry-perry",fullName:"Henry Perry"},{id:"311210",title:"MSc.",name:"Maria",surname:"Vincent",slug:"maria-vincent",fullName:"Maria Vincent"},{id:"311211",title:"Dr.",name:"Jose",surname:"Quintero",slug:"jose-quintero",fullName:"Jose Quintero"},{id:"311212",title:"Dr.",name:"James",surname:"Rynerson",slug:"james-rynerson",fullName:"James Rynerson"}],corrections:null},{id:"70037",title:"Hyperosmolarity of the Tear Film in the Dry Eye",doi:"10.5772/intechopen.90113",slug:"hyperosmolarity-of-the-tear-film-in-the-dry-eye",totalDownloads:483,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The dry eye is a complex multifactor illness of the tear film and of the ocular surface characterized by symptoms of discomfort, vision alterations, and instability of the pre-corneal tear film which may bring about potential damage on the ocular surface. Instability of the film will produce increasing osmolarity of the tear film which will trigger epithelium osmotic lesions and inflammation. As these changes take place on the ocular surface, neurophysiologic mechanisms of homeostasis will be altered which will complicate the process even further with the cropping of vicious physiopathologic circuits.",signatures:"Alejandro Aguilar and Alejandro Berra",downloadPdfUrl:"/chapter/pdf-download/70037",previewPdfUrl:"/chapter/pdf-preview/70037",authors:[{id:"308539",title:"Ph.D.",name:"Alejandro",surname:"Aguilar",slug:"alejandro-aguilar",fullName:"Alejandro Aguilar"},{id:"308918",title:"Dr.",name:"Alejandro",surname:"Berra",slug:"alejandro-berra",fullName:"Alejandro Berra"}],corrections:null},{id:"70865",title:"Recent Advances in the Effects of Various Surgical Methods on Tear Film after Pterygium Surgery",doi:"10.5772/intechopen.90635",slug:"recent-advances-in-the-effects-of-various-surgical-methods-on-tear-film-after-pterygium-surgery",totalDownloads:554,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Pterygium is a common ocular disorder with a high prevalence. Surgical resection is the main method of treating pterygium. Recurrence rate of traditional surgical methods such as simple excision of pterygium is high. In recent years, amniotic membrane transplantation, autologous limbal stem cell transplantation, application of mitomycin (MMC) and some other methods become commonly used. Autologous limbal stem cell transplantation is being most widely used. Pterygium has a close relationship with dry eye, and dry eye is one of the important reasons for its recurrence. Different surgical methods have different effects on postoperative tear film. This review will summarize the recent points.",signatures:"Juan Wang",downloadPdfUrl:"/chapter/pdf-download/70865",previewPdfUrl:"/chapter/pdf-preview/70865",authors:[{id:"310482",title:"Dr.",name:"Juan",surname:"Wang",slug:"juan-wang",fullName:"Juan Wang"}],corrections:null},{id:"70513",title:"Molecular Genetics of Keratoconus: Clinical Implications",doi:"10.5772/intechopen.90623",slug:"molecular-genetics-of-keratoconus-clinical-implications",totalDownloads:580,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Occurrence of keratoconus is pan-ethnic with reported prevalence ranging widely from 1:400 to about 1:8000, higher in Asian than Western populations. Its genetics is complex with undefined pattern of inheritance. Familial traits are also known. More than 50 gene loci and 200 variants are associated with keratoconus, some through association studies with quantitative traits of cornea features including curvature and central thickness. Environmental, behavioral, and epigenetic factors are also involved in the etiology, likely interactively with genetic susceptibility. Regardless of sex and age of disease onset, clinical courses and responses to treatment vary. Keratoconus is a major cause of cornea transplantation and is potentially blinding. Currently collagen cross-linking provides effective treatment although responses from some patients can be unpredictable with complications. Early diagnosis is vital to obtain good treatment outcome, but in many patients early signs and symptoms are not obvious. While there are potential biomarkers, reliable pre-symptomatic detection and prediction of treatment response may require multitude of gene variants, cornea properties, and external risk factors.",signatures:"Yu Meng Wang and Calvin C.P. Pang",downloadPdfUrl:"/chapter/pdf-download/70513",previewPdfUrl:"/chapter/pdf-preview/70513",authors:[{id:"231722",title:"Ph.D.",name:"Calvin C.P.",surname:"Pang",slug:"calvin-c.p.-pang",fullName:"Calvin C.P. Pang"},{id:"315108",title:"Dr.",name:"Yu Meng",surname:"Wang",slug:"yu-meng-wang",fullName:"Yu Meng Wang"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"8855",title:"Retinoblastoma",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"1686b2f1d697de9d4bc2005a5fa9b998",slug:"retinoblastoma-past-present-and-future",bookSignature:"Hind Manaa Alkatan",coverURL:"https://cdn.intechopen.com/books/images_new/8855.jpg",editedByType:"Edited by",editors:[{id:"223782",title:"Dr.",name:"Hind",surname:"Alkatan",slug:"hind-alkatan",fullName:"Hind Alkatan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6372",title:"Early Events in Diabetic Retinopathy and Intervention Strategies",subtitle:null,isOpenForSubmission:!1,hash:"46ff48bdb1bac8a69372566fff0e2f6d",slug:"early-events-in-diabetic-retinopathy-and-intervention-strategies",bookSignature:"Andrew T.C. 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\n
1. Introduction
\n
Poultry sector is the source of animal proteins in the form of meat and eggs. The total strength poultry in Pakistan is 1210 million. The poultry sector provides 1,391,000 tons of meat and 18,037 million eggs annually. The contribution of poultry sector in agriculture and livestock sectors is 7.5 and 12.7%, respectively, while its contribution in total GDP is 1.4. The annual growth rate of poultry sector is 5–10% in the country. The poultry meat contributes 32.7% of total meat production in the country [1]. The demand of poultry meat has increased over the years due to the increasing demand of quality food in the form of meat and eggs.
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Poultry birds being living creatures are prone to infections. Diseases are a cause of high economic losses to poultry farmers [2]. In developing countries, poultry diseases are a cause of very large economic losses to poultry industry [3, 4]. Among bacterial, viral, parasitic and fungal diseases, the outbreak of viral diseases can cause havoc to the poultry industry causing reduced meat and egg production. The important viral diseases of poultry include Newcastle disease (ND), avian influenza, infectious bursal disease (IBD), infectious bronchitis (IB), etc. The high prevalence of diseases creates major constraints in the development of poultry sector. Immunization is the use of a biological preparation in the form of vaccine for enhanced immunity and prophylactic measures against specific diseases [5]. The process of injecting the vaccine in the body is known as vaccination. Proper vaccination can prevent losses due to diseases in poultry flocks [6]. Mostly, the vaccines are carried out against viral diseases but vaccines against salmonella, mycoplasma and coryza infections are also available. The vaccines against parasitic infections like coccidiosis are also being tested in different countries.
\n
Vaccination is one of the most important tools for preventing diseases and in reducing the economic losses of the poultry producers [2]. Vaccination comprises the use of attenuated, killed, or recombinant organisms for stimulation of the body’s immune response that recognizes the injected organism as a foreign antigen, resulting in clearing the antigen and developing memory cells in the body. Vaccination is the cheapest, reliable, effective, economical, affordable and suitable alternate for prevention of diseases in poultry flocks [5].
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Live vaccines comprise a virulent virus whose pathogenicity has been weakened through consecutive cultures in living cells but the virus maintains its immunogenic antigenicity for stimulating the body’s immune response; this whole process is commonly known as attenuation [7]. Commonly used live vaccines against diseases of poultry are Newcastle disease, infectious bronchitis, infectious bursal disease, etc. [8].
\n
Killed vaccines comprise viruses whose pathogenicity has been inactivated through the use of physical and chemical means, but the protein coat structure has been maintained, which acts immunogenic. The viruses are physically inactivated by the use of ultraviolet radiations and heat and through chemical means by the use of formalin [9]. Killed vaccines against Newcastle disease and Avian Influenza are being used and have an advantage of providing long term immunity to flocks.
\n
Vaccine failure is the consequence of the inability of the chicken to develop adequate immunity after immunization or susceptibility of bird to field outbreak after administration of vaccine [3]. High rates of 53.5% of vaccination failures have been recorded in vaccinated poultry flocks. Rates of 25.6, 25.6 and 2.3% of vaccine failure in Newcastle disease, infectious bursal disease (Gumboro) and fowl pox, respectively, have been recorded [2]. The common breaches in transportation, handling, storage and administration of vaccines are responsible for high rates of vaccine failure in poultry flocks in developing countries [2].
\n
\n
\n
2. Causes of vaccine failure
\n
The causes of vaccine failure can be categorized into two major factors: antigen factor and host response.
\n
\n
2.1. Antigen factors
\n
The protective vaccine antigen is of prime importance in the production of effective vaccine. The vaccines available in the market may have the following shortcomings resulting in vaccine failure.
\n
\n
2.1.1. Improper formulation of vaccine
\n
The vaccines are manufactured in a processing plant where the titer of antigen of specific virus or bacteria may not be maintained properly; as a result, the inoculums may not initiate protective immune response in birds. The titer of antigen in the vial of vaccine may be low which results in low immunity level in birds. The dose–response relationship among the virus content, serological response and clinical protection has been reported [10]. Virus concentration has a significant effect on immunogenicity of vaccines [11]. The inadequate procedure of formulation of vaccine and lack of standard procedures of vaccine formulation result in the production of nonpotent vaccine.
\n
\n
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2.1.2. Nonusage of local antigens
\n
Some of the viral diseases of poultry like infectious bursal disease and salmonella have many serotypes. Some of the serotypes are prevalent in one area, while others are prevalent in other areas. The local disease causing agents in any area are of prime importance for vaccine manufacturing. The strains of viruses differ from area to area. The local serotypes and locally isolated antigens are considered the most suitable immunogens for formulating vaccines. The nonusage of local vaccine antigens may result in disease outbreaks [2]. The foreign vaccine may be made from serotypes that are different from field strain [12]. Moreover, vaccination with foreign vaccine may not provide immunity to birds if the field strain is of higher virulence and of a different nature [13].
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\n
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2.1.3. Improper storage temperature
\n
After the formulation of the vaccine, its storage is of utmost importance. The freeze-dried vaccines require freezing temperatures, while lyophilized vaccines may be stored at 4°C, and during transportation the low temperature might not be properly maintained. The Marek’s disease vaccine is stored in liquid nitrogen at very low temperatures, while live vaccines of ND, IBD, IB, etc. are stored at 4–8°C. The oil-based vaccines may be stored below 8°C. In the poultry sector, almost all the vaccines available are thermolabile in nature. The maintenance of proper cold chains and storage temperature is a prerequisite for optimal potency of vaccines. The shortage of electricity, weak, nonfunctional, obsolete and repaired storage equipment, high temperature during transport, refrigerators without thermometers, etc. are the common problems of vaccine storage of developing countries like Malaysia, India, Tanzania and Pakistan [14, 15, 16, 17, 18]. Data have been recorded about use of vaccines after purchase from the market in Nigeria, and it has been found that 16% of farmers do not perform vaccination on the date of purchase of vaccine and 7% of farmers store the vaccine on the shelf without proper preservation, thus resulting in vaccine failure [2].
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2.1.4. Exposure to direct sunlight
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It has been documented that vaccines are transported like ordinary drugs [2]. Direct sunlight has UV radiations which are lethal for live viruses. The exposure of vaccine to direct sunlight results in the killing of antigens present in the vial, and as a result, the number of viral antigens is reduced in the vaccine and the vaccine may become ineffective.
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2.1.5. Use of expired vaccines
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The potency of vaccines is maintained to a certain period of time, provided that the transportation and storage temperature is properly maintained. The use of vaccines after the date of expiry may not result in optimal immune response and can also result in vaccine failure.
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2.1.6. Mutation of viruses
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Some of the viruses like the influenza virus are of a mutating nature and as a result pose a serious threat regarding the effectiveness of vaccine against certain diseases.
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2.2. Host factors
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The poultry birds to be vaccinated against diseases may not respond effectively against vaccines due to the following shortcomings, thus resulting in vaccine failure.
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2.2.1. Stress on birds
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Stress is a condition of vulnerable homeostasis and is affected by management and environment factors. Birds normally have limited resources in the body for growth, response to environment changes and maintain a defense system for diseases. The stress on birds can be due to a number of factors including cold stress, heat stress, high humidity, transportation stress, intensive farming, high stocking density, overcrowding, low per bird space, decreased ventilation, poor litter conditions, accumulation of bad smell in sheds and poultry houses, off feeding, water deprivation, poor management, bad sanitary conditions, very wet or extremely dry litter, dusty environment, parasitism, nutritional deficiency, fever, and so on. In these cases, there can also be vaccine failure in livestock. The poultry birds are sensitive to both cold and warm weather [3]. Heat stress is an important factor of economic loss for the producer [19], while cold stress modifies the immune response of broilers [20]. The symptoms of stress in birds include panting, increased thirst, reduced appetite, reduced egg production, decreased weight gain, small sized eggs, thin egg shells, reduced growth, prostration, etc. All the factors including management conditions, substandard hygienic conditions, etc. contribute to the possible causes of high economic losses by leading to vaccine failure [21].
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2.2.2. Concurrent disease
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It is highly important that the vaccination should be done in healthy birds. The vaccination in sick and diseased birds may not provide fruitful results; rather, vaccine reaction may occur leading to extra stress and an increased morbidity and mortality rate. Moreover, any other disease condition may also contribute to vaccine failure. When the birds are morbid due to the same disease for which vaccination had been done, then there will also be vaccine failure because the antibodies produced against the pathogenic agent will neutralize the antigen of vaccine and a reaction may take place in the body of birds and vaccination may worsen the condition of disease.
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2.2.3. Immunosuppressive diseases
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Certain diseases are immune-suppressive in poultry flocks like mycotoxicosis, infectious bursal diseases (Gumboro), chicken infectious anemia, Marek’s disease, etc. These immune suppressive diseases may also lead to vaccine failure. The fungal toxins present in poultry feed have a bad effect on the feed conversion, growth, health and immune status. The fungal toxins cause the following effects: carcinogenic, allergic, hypersensitivity and depression. The common age of infection of infectious bursal disease (Gumboro) in poultry flock is at 3rd to 7th week of age. The bursa is a lymphoid organ in poultry where maturation of B cells takes place in poultry. The infection of IBD during this stage of age may lead to permanent damage to bursa; as a result, the maturation of B Cells may not take place in birds throughout their life span and thus the birds remain prone to vaccine failure during the rest of their lives.
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2.2.4. Immaturity of birds
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The receptors for some antigens develop in the body with advancing age. Some of receptors of virus develop as early as with the hatch of a chick. The receptors of diseases like Newcastle disease, infectious bronchitis, etc. develop at a very early age while the receptors of diseases like infectious bursa disease, fowl pox, etc. develop late in the body. Vaccination at a very early age before the development of certain receptors may also result in vaccine failure. The age of the bird is very important at the time of vaccination.
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2.2.5. Interaction with maternal antibodies
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The antibodies of certain viral diseases are transmitted through eggs. As the breeder/parent flocks of poultry are routinely vaccinated against viral diseases which are prevalent in the area, the newly hatched chicks have maternal antibodies in their blood and these can interact with vaccine antigens. The antibodies against ND virus and IBD virus are transmitted in eggs and provide protection to the newly hatched chicks during the first week of birth. High maternal antibodies interfere with multiplication of live vaccines and reduce the level of immunity production in the chicks. The use of live vaccines during the first week of birth in chicks against diseases whose maternal antibodies still persist in the body of the chick will result in neutralizing of antigen and active immunity may not be provided by the vaccine [22].
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2.2.6. Improper route of administration
\n
The vaccines have specific routes for their administration in the body of the bird, that is, through oral, subcutaneous (S/C), intramuscular (I/M), wing web (W/W), drinking water (D/W), eye dropping (E/D), spray, etc. Not following f specific recommended routes of vaccination may result in vaccine failure in poultry flocks. The fault of administering the vaccine also results in vaccine failure [3, 4].
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\n
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2.2.7. Inadequate dosage
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If the optimum dose of vaccine had not been injected in the bird, then there is also failure of vaccine. Overdosage may lead to reaction, and underdosage can lead to vaccine failure. There are certain factors which cause reduction in optimal vaccine dosage, that is, use of chlorinated water for vaccination, use of water having antimicrobial contents, etc. Moreover, in the case of injecting vaccine to more number of birds than recommended by the company or manufacturer, the low dose will be available to the whole the flock and thus may be prone to low vaccine titers and vaccine failure.
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2.2.8. Lack of booster dose
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Some of the vaccines require a booster dose for successful immunization. The booster dose is required after 10–20 days of the initial dose. The initial dose is required for priming of vaccine while the booster is required for maximum protection against antigen. The lack of booster dose results in low antibody titers, resulting in vaccine failure.
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2.2.9. Wrong timing of vaccination
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Mostly the vaccines should be done early in the morning or later if it is during summer. The birds feel comfortable during cold hours of the day. As a result, a good response is obtained after vaccination. Otherwise, the chances of vaccine failures are increased in the case of vaccinating birds during the hot hours of the day.
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2.2.10. Climatic factors
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The climate variation is a change in climatic parameters (temperature, rainfall, humidity and soil moisture) [23]. Climate change affects both living and nonliving creatures, thus contributing to the health of poultry flocks and may lead to vaccine failure and disease outbreaks.
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3. Preventing vaccine failure
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The following procedures can prevent vaccine failure in livestock and poultry flocks.
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3.1. Vaccine factors
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3.1.1. Proper formulation of vaccine
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The vaccines must be properly formulated. The dosage of vaccinal antigen and properly processed vaccines provide good results and prevent vaccine failure. The record of all batches of vaccines and their standard tests of vaccine potency may be maintained. Moreover, the titer of antigen should be optimal so that the proper immunity level may be provided by the vaccine.
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3.1.2. Use of local strains of viruses
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For maximum immune protection, the local strains of antigens must be used for manufacturing of vaccine. The local disease causing agents of any area are specific targeted pathogens and antigens from local disease outbreaks and provide maximum protection against local disease causing organisms.
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3.1.3. Adequate procedure of vaccine formulation
\n
The viruses used for vaccine production are harvested in live cells like chicken embryo. The bacteria used for vaccine production are culture in growth media like nutrient agar, etc. Similarly, the procedures for live attenuated, killed inactive vaccines, subunit vaccines differ from antigen to antigen. The adequate procedure for vaccine formulation will result in a maximum immune response from the antigen and hence a successful immune response.
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3.1.4. Proper storage and cold chain temperature
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Vaccines are to be manufactured in a plant and then after stored and transported to remote areas. Temperature has direct effect on the efficacy of vaccine [24]. The vaccines lose their potency with the passage of time; hence, they require proper cold temperatures to remain stable and viable for long periods of time. The proper storage and cold chain temperature of vaccine is of utmost importance; the vaccines must be stored below 4°C. The storage of food items, chemotherapeutic agents, specimens for pathological examinations, tissue samples for laboratory findings along with vaccine should be avoided [25]. During transportation, the maintenance of cold chain is a challenge for developing countries. A number of factors create hurdles in maintaining cold chain systems including loss of electric power, substandard refrigeration system, overchilling, etc. Moreover, the extra chilling of oil-based vaccines results in crystal formation of adjuvant material of vaccine like aluminum salts, etc. resulting in reduced potency of vaccines. The thermostable vaccines can be stored at 2–8°C and has more significance where cold chain temperature is not maintained and is less expensive [24]. Thermostable vaccines have some resistance to cold and hot environments, while freeze-dried vaccines should be preserved and stored at low temperatures in the refrigerator at 4°C and even during the transport of vaccine the cooling/ice blocks should be used to maintain low temperatures during transportation of vaccine. Freezing and thawing must be avoided. The vaccines must only be brought out of the refrigerator/freezer at the time of use at the farm. The live vaccines in poultry flocks must be used within 2 h of its reconstitution. Once they have been reconstituted, they drop their potency rapidly. The reconstituted vaccines should be used as early as possible and unused vaccines may be stored in the refrigerator for a maximum of 6 h; after that period the vaccines should be discarded.
\n
The use of thermostable vaccines can be an alternative to overcome the difficulties related to cold chain and storage temperature [26]. The thermostable vaccines can maintain their potency and vaccinal activity for 1 year at 2–8°C and for 3 months up to 28°C in dried form [27]. Routes including intraocular, intranasal, paternal (injection) and oral (drinking water and feed) can be used for administration of thermostable vaccines [28, 29].
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3.1.5. Avoiding exposure to direct sunlight
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Direct exposure of sunlight results in the killing of antigen present in the vial; as a result, the titer of vaccine antigens are reduced in the vaccine and it may become ineffective. During formulation of solution for oral or parental vaccines, direct exposure to sunlight should be avoided and for oral vaccines the cap of the vaccine vial should be opened inside water. The vaccines should be mixed in drinking water in a room or in a shady place; moreover, during the transportation of vaccine, black or colored bags and cartons should be used to prevent sunlight affecting the vaccine.
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3.1.6. Avoiding use of expired vaccines
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The date of expiry mentioned on the vial of vaccine should be checked before opening the vaccine vial. The expired vaccines should be discarded or returned to the manufacturers. At places where vaccines are frequently used, it should be a practice to purchase a fresh stock of vaccines. Some oil-based vaccines have a very narrow range of shelf life of 3–6 months. While some lyophilized live vaccines have longer shelf life of 1–2 years, provided the vaccines are stored at proper temperatures. The use of expired vaccines should be avoided [25].
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3.1.7. Use of adjuvant
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Adjuvants are substances that are added in the vaccine to increase the bioavailability of vaccine. In the poultry sector, the oral route of vaccination is followed for most of the vaccines. The oral route of vaccine delivery is difficult due to barriers in the gastrointestinal tract. In order to overcome this challenge, the antigen must be protected from such an environment and the immune response must be activated. This challenge can be overcome by the use of adjutants. Adjuvants improve the safety of the vaccine and have a potential effect on inducing mucosal immune response [30]. The use of adjuvants provides good results for live vaccines. The adjuvants enhance the availability of vaccine and act as a sticking agent for vaccine and the mucous membranes of the body.
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3.1.8. Use of stabilizers
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Stabilizers are substances which are added in a vaccine to increase the shelf life of the vaccine. The stabilizers like Vac-Safe (Intervet), Vital Blue, etc. can be used for oral live vaccines like ND, IBD, IB, etc. of poultry. The skimmed milk at the rate of 2 g/L can also be added as a suitable alternative stabilizer [31].
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3.1.9. Manufacturer guidelines
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The company’s manufacturing guidelines provide valuable information regarding vaccine efficacy, usage, storage and route. The guidelines are: (1) open the vaccine vial in water and (2) use one complete vial after opening it. The vaccines must be utilized as early as possible after its reconstitution in diluents, etc. Once the vaccine is reconstituted, the time limit is set. Vaccines must be used within 2 h of their reconstitution during winter and within 1 h of their reconstitution during summer. IB vaccines lose potency after 1 h of their reconstitution, while pox vaccines lose 50% of their potency after 1 h of their reconstitution [32].
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3.1.10. Use of immune boosters
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There are many substances that have been used in poultry for immune stimulation. Some of them are vitamin E, selenium and levamisole [33, 34]. The selenium supplementation has effect on enhancing humoral immune response in chicks [35, 36]. The selenium supplementation increased natural resistance of increasing response of organisms to antigenic stimuli [37, 38]. The increased humoral antibody titers are observed when selenium is used in feed [39].
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3.1.11. Booster dose
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Some of the vaccines require a booster dose for successful immunization [2]. The booster dose is required after 10–20 days of the initial dose. The initial dose is required for priming of vaccine, while the booster is required for maximum protection against antigen. The lack of booster dose results in low antibody titers. As a result, vaccine failure may result. It has been documented that the priming with live attenuated vaccine followed by booster of killed vaccine and second booster with live vaccine provides best protection against Newcastle disease [40]. However, subsequent inoculums are also required at regular intervals.
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3.2. Host factors
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An effective vaccine response may be obtained if the bird is healthy. The following recommendations/guidelines can overcome the shortcomings regarding prevention of vaccine failure.
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3.2.1. Stress-free birds
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All types of stresses mentioned earlier should be avoided before administration of vaccines to poultry birds. The temperature of the environment and sheds should be normal before vaccination. Moreover, the birds should be in a good physical condition before administration of vaccines. Stress suppresses the chicken’s immune response, and during these conditions of stress, birds should not be vaccinated [41]. The stress on birds can be minimized by the use of vitamins and minerals in drinking water before, during and after vaccination [13].
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3.2.2. Deworming before vaccination
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The adult birds may be dewormed before vaccination at least 15 days before injection of vaccine; moreover, diseased birds should be treated properly and be given vaccines after recovery. Only healthy flocks should be vaccinated.
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3.2.3. Monitoring of subclinical infections
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Some of the diseases in poultry have subclinical infections, like coccidiosis. The birds apparently seem health, but subclinical infections persist in birds over long periods of time, which have previously been infected with coccidiosis infections. On the day of vaccination, the birds should be closely monitored. The apparent health of flock should be analyzed. Moreover, the color and consistency of fecal droppings, abnormal sounds from birds, respiratory distress, etc. should be evaluated. After being satisfied with the proper health status of the bids, the concerned staff may be allowed to vaccinate the flock.
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3.2.4. Balanced feed
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Nutrition plays a significant role in the development and function of the immune system [42]. The commercial feed offered to poultry should be analyzed regularly and the level of toxins be checked on a regular basis. Especially in summer and humid environment conditions, the fungus grows on feed ingredients and fungal metabolites gain entry into the body of poultry, and as a result, they cause immune-suppression, decreased growth, hypersensitivity and decreased feed intake.
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3.2.5. Maturity of bird
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In poultry birds, age is considered for the vaccination of bird; receptors for different pathogens develop in the body of poultry bird at specific ages, so the vaccination is done keeping in view the age of the bird, that is, ND + IB vaccine is done on the first day of birth. Similarly, the Marek’s disease vaccine is done immediately after hatching of chicks in the hatchery machine. The IBD (infectious bursal disease/Gumboro) vaccine is done at 10–12 days of birth and booster is given after 10 days. In broiler birds, the hydropericardium syndrome (HPS)/Angara vaccine is done at 21–23 days of birth. So, the age of the bird is very important for vaccination. The domestic/rural poultry requires injection of ND after every 2–2.5 months.
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3.2.6. Consideration of maternal antibodies
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As the breeder/parent flocks of poultry are routinely vaccinated against viral diseases which are prevalent in the area, the newly hatched chicks have maternal antibodies in their blood. It is suggested that the bird should be a minimum 11 days old at the time of administration of IBD vaccine and 7 days old at the time of administration of ND vaccine [31].
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3.2.7. Proper vaccination schedule
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In Pakistan, the outbreak of diseases like infectious bronchitis and avian influenza occurs in birds during winter; for that purpose, the birds must be vaccinated prior to winter, so that proper antibody titer may be reached in birds before exposure to the disease causing virus or bacteria in birds. To avoid any economic loss, a record may be maintained and a strict vaccination schedule according to disease prevalence in the area must be followed in poultry flocks [43].
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3.2.8. Preparation of flocks for vaccination
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The poultry flocks are properly prepared for administration of oral vaccines. The birds are offered feed and are kept off water for 2 h before administration of vaccines. The drinkers are properly washed and the vaccine is given to birds. The number of drinkers is increased in order to ensure that all the birds drink vaccine water. The water should be provided to birds in such a way that birds drink all the vaccine water within 2 h. The birds are regularly moved during this process so that all the birds drink water containing the vaccine virus. The stabilizers and coloring agents can be added in the vaccine. A tinge of the coloring agent can also be noticed on the beak of birds which indicates the drinking of water.
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3.2.9. Host resistance
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Certain genes are discovered which have genetic resistance against viral diseases of poultry [44]. The breeding for disease resistance may provide good long-term solutions for disease control [45]. However, the emergence of new genetic groups and mutations require new vaccine practices for successful immunization [46].
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3.2.10. Vitamin and mineral supplementation
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Vitamin and mineral supplements help to develop immune response by acting on the immune cell or by changing metabolic or endocrine functions [47]; as a result, the antibodies are produced in the body at a faster rate and a protective level of antibodies is gained in a shorter time. Vitamin E and selenium have a role in modulating the immune response and have shown good results in preventing vaccine failure. Research conducted shows that vitamin E may enhance immune response to antigens in cockerels but excessive vitamin E may depress specific immune responses [48]. Administration of excess vitamins, amino acids, minerals and their combinations enhance the disease resistance by stimulating humoral and cellular immunity and phagocytosis [49]. Optimal vitamin nutrition is required for optimal immune response and disease resistance. The addition of higher levels of vitamin A, C, E and Selenium ensures better immune response of birds to vaccination and reduces the chances of vaccination failure in broiler poultry flocks [50]. Studies have suggested that the nutrient levels that are adequate for growth and feed efficiency may not be adequate for normal immunity for maximizing the resistance to disease [51, 52].
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3.2.11. Continuous surveillance
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The regular and continuous surveillance of prevalent diseases should be conducted in order to collect data on the disease pattern. For this purpose, the blood/serum and fecal samples may be collected and sent to the laboratory for diagnosis of disease. Moreover, the tracheal and cloacal swabs can also be sent to the laboratory for isolation of pathogens. The antibodies titer against injected vaccines may be got routinely checked for maintaining optimum titer of antibody against the disease.
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3.2.12. General precautions
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Considerations regarding the use of live and killed vaccines should also be kept in mind during vaccination. The live vaccines may cause vaccine reactions and injection of killed vaccines may cause local tissue reactions. Therefore, only an expert professional or qualified veterinary assistant should be allowed to vaccinate the poultry birds. In general, vaccination should be done during early hours of the day or late hours after noon during summer. Vaccination during hot hours of the day may not give good results. Moreover, after transportation of birds, the birds should be given proper rest before vaccination [2].
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4. Conclusion
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Vaccination may be considered as insurance against diseases. A successful vaccination program is dependent on many factors including vaccine handling, quality and nature of vaccine, use of local antigens, immunogenic response inside the body of the bird and following manufacturers’ instructions. Although the disease outbreaks against specific diseases in nonvaccinated flocks cause very high economic losses, the severity of disease outbreaks in properly vaccinated flocks is low. The potential threat of disease outbreaks even in vaccinated flocks cannot be avoided 100%, but the losses can be minimized through thoughtful consideration of success of vaccination program for poultry flocks. In Pakistan, there is a high incidence and prevalence of contagious diseases of poultry and vaccination is the only tool to prevent birds from diseases. Through preventing vaccine failure, the productivity of food items like meat and eggs can be increased in the country, and shortage of animal protein can be overcome and thus per capita availability of eggs and meat can be increased. Moreover, the poultry sector can play a better role in the economy of the country by decreasing economic losses due to vaccine failure, thus increasing annual share in GDP value and becoming a major contributor of the agricultural sector of the country.
\n
\n\n',keywords:"immunization, vaccine failure, poultry",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/62561.pdf",chapterXML:"https://mts.intechopen.com/source/xml/62561.xml",downloadPdfUrl:"/chapter/pdf-download/62561",previewPdfUrl:"/chapter/pdf-preview/62561",totalDownloads:3546,totalViews:2250,totalCrossrefCites:5,totalDimensionsCites:9,totalAltmetricsMentions:3,impactScore:6,impactScorePercentile:94,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"February 16th 2018",dateReviewed:"June 6th 2018",datePrePublished:"November 5th 2018",datePublished:"November 28th 2018",dateFinished:"July 10th 2018",readingETA:"0",abstract:"Poultry sector is very useful for humans in terms of production of food items like meat and eggs. Pakistan has a developing poultry sector and is the second important sector after the textile industry. The poultry sector is encountered with many challenges; among them is the high incidence of disease outbreaks that result in colossal economic losses. The diseases of commercial and rural poultry include Newcastle disease (ND), infectious bursal disease (IBD), fowl pox, Marek’s disease, infectious bronchitis (IB), avian influenza, hydropericardium syndrome, etc. The disease outbreaks have also occurred in vaccinated flocks. Better understanding of the causes of vaccine failure will result in identifying prophylactic measures regarding disease outbreaks in poultry flocks. This chapter overviews the common causes of vaccine failure and further highlights the procedures for successful immunization.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/62561",risUrl:"/chapter/ris/62561",book:{id:"7234",slug:"immunization-vaccine-adjuvant-delivery-system-and-strategies"},signatures:"Aamir Sharif and Tanveer Ahmad",authors:[{id:"246237",title:"Dr.",name:"Aamir",middleName:null,surname:"Sharif",fullName:"Aamir Sharif",slug:"aamir-sharif",email:"aamirsharifcheema@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"259271",title:"Dr.",name:"Tanveer",middleName:null,surname:"Ahmad",fullName:"Tanveer Ahmad",slug:"tanveer-ahmad",email:"tanveeruaf@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Causes of vaccine failure",level:"1"},{id:"sec_2_2",title:"2.1. Antigen factors",level:"2"},{id:"sec_2_3",title:"2.1.1. Improper formulation of vaccine",level:"3"},{id:"sec_3_3",title:"2.1.2. Nonusage of local antigens",level:"3"},{id:"sec_4_3",title:"2.1.3. Improper storage temperature",level:"3"},{id:"sec_5_3",title:"2.1.4. Exposure to direct sunlight",level:"3"},{id:"sec_6_3",title:"2.1.5. Use of expired vaccines",level:"3"},{id:"sec_7_3",title:"2.1.6. Mutation of viruses",level:"3"},{id:"sec_9_2",title:"2.2. Host factors",level:"2"},{id:"sec_9_3",title:"2.2.1. Stress on birds",level:"3"},{id:"sec_10_3",title:"2.2.2. Concurrent disease",level:"3"},{id:"sec_11_3",title:"2.2.3. Immunosuppressive diseases",level:"3"},{id:"sec_12_3",title:"2.2.4. Immaturity of birds",level:"3"},{id:"sec_13_3",title:"2.2.5. Interaction with maternal antibodies",level:"3"},{id:"sec_14_3",title:"2.2.6. Improper route of administration",level:"3"},{id:"sec_15_3",title:"2.2.7. Inadequate dosage",level:"3"},{id:"sec_16_3",title:"2.2.8. Lack of booster dose",level:"3"},{id:"sec_17_3",title:"2.2.9. Wrong timing of vaccination",level:"3"},{id:"sec_18_3",title:"2.2.10. Climatic factors",level:"3"},{id:"sec_21",title:"3. Preventing vaccine failure",level:"1"},{id:"sec_21_2",title:"3.1. Vaccine factors",level:"2"},{id:"sec_21_3",title:"3.1.1. Proper formulation of vaccine",level:"3"},{id:"sec_22_3",title:"3.1.2. Use of local strains of viruses",level:"3"},{id:"sec_23_3",title:"3.1.3. Adequate procedure of vaccine formulation",level:"3"},{id:"sec_24_3",title:"3.1.4. Proper storage and cold chain temperature",level:"3"},{id:"sec_25_3",title:"3.1.5. Avoiding exposure to direct sunlight",level:"3"},{id:"sec_26_3",title:"3.1.6. Avoiding use of expired vaccines",level:"3"},{id:"sec_27_3",title:"3.1.7. Use of adjuvant",level:"3"},{id:"sec_28_3",title:"3.1.8. Use of stabilizers",level:"3"},{id:"sec_29_3",title:"3.1.9. Manufacturer guidelines",level:"3"},{id:"sec_30_3",title:"3.1.10. Use of immune boosters",level:"3"},{id:"sec_31_3",title:"3.1.11. Booster dose",level:"3"},{id:"sec_33_2",title:"3.2. Host factors",level:"2"},{id:"sec_33_3",title:"3.2.1. Stress-free birds",level:"3"},{id:"sec_34_3",title:"3.2.2. Deworming before vaccination",level:"3"},{id:"sec_35_3",title:"3.2.3. Monitoring of subclinical infections",level:"3"},{id:"sec_36_3",title:"3.2.4. Balanced feed",level:"3"},{id:"sec_37_3",title:"3.2.5. Maturity of bird",level:"3"},{id:"sec_38_3",title:"3.2.6. Consideration of maternal antibodies",level:"3"},{id:"sec_39_3",title:"3.2.7. Proper vaccination schedule",level:"3"},{id:"sec_40_3",title:"3.2.8. Preparation of flocks for vaccination",level:"3"},{id:"sec_41_3",title:"3.2.9. Host resistance",level:"3"},{id:"sec_42_3",title:"3.2.10. Vitamin and mineral supplementation",level:"3"},{id:"sec_43_3",title:"3.2.11. Continuous surveillance",level:"3"},{id:"sec_44_3",title:"3.2.12. General precautions",level:"3"},{id:"sec_47",title:"4. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Anonymous 2017. Economic Survey of Pakistan, Ministry of Finance, Government of Pakistan, Islamabad, Pakistan; 2017\n'},{id:"B2",body:'Bosha JA, Nongo NN. Common breaches in poultry vaccine handling and administration in Makurdi metropolis: A recurrent phenomenon in the tropics. Vom Journal of Veterinary Sciences. 2012a;9:11-16\n'},{id:"B3",body:'Abdullahi US, Adamu SB, Ahmed AF. Investigations on some causes of poultry vaccination failures in Bauchi metropolis and environs, Nigeria. Nigeria Journal of Experimental and Applied Biology. 2009;10:47-50\n'},{id:"B4",body:'Bosha JA, Nongo NN. Investigating vaccine handling and administration in Makurdi metropolis, Benue state, Nigeria. 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Effect of selenium and vitamin E on the development of immunity to coccidiosis in chickens. Poultry Science. 1984;63:1136-1143\n'},{id:"B38",body:'Madron P, Vrzgulova N. Vitamin E and Selenium Increase the Natural Resistance of Farm Animals. Vol. 38. Veterinarskvi; 1988. pp. 369-371\n'},{id:"B39",body:'Schrauzer GN. Selenomethionine: A review of its nutritional significance, metabolism and toxicity. Journal of Nutrition. 2000;130:1653-1656\n'},{id:"B40",body:'Afzal F, Saliha U, Fawad N, Ahmed S, Rehman HU, Munawar J, Naheed G, Siddique B. Isolation, characterization of Newcastle disease virus and comparative efficacy of different vaccine regimes in broiler birds. Journal of Animal and Plant Science. 2015;25:971-976\n'},{id:"B41",body:'Zhao Y, Andre JA, Dijkman AR, Fabri T, Mart CM, Peter WG. Effects of temperature, relative humidity, absolute humidity and evaporation potential on survival of airborne Gumboro vaccine virus. Applied Environmental Microbiology. 2011;20:1048-1054\n'},{id:"B42",body:'Khan SA, Iqbal M, Ashraf SK. Poultry industry in Pakistan. Agro Vet News. 1993;5(6):9\n'},{id:"B43",body:'Morangon S, Busani L. The use of vaccination in poultry production. Revue scientifique et technique (International Office of Epizootics). 2006;26:265-274\n'},{id:"B44",body:'Cheng H. Viral diseases in chickens. In: Breeding for Disease Resistance in Farm Animals. Chapter 5 (3rd Edition). Wallingford, Oxford shire, UK: Commonwealth Agricultural Bureaux International (CABI); 2010. pp. 70-82\n'},{id:"B45",body:'Rasool F, Nizamani ZA, Soomro NM, Afzal F, Parveen F, Rahman S. Susceptibility of desi and commercial layer breeds to low pathogenicity avian influenza virus infection. Journal of Animal and Plant Science. 2014;24(6):1643-1648\n'},{id:"B46",body:'Munir M, Cortey M, Abbas M, Qureshi ZA, Afzal F, Shabbir MZ, Khan MT, Ahmed S, Ahmad S, Baule C, Stahl K, Zahori S, Berg M. Biological characterization and phylogenetic analysis of a novel genetic group of Newcastle disease virus isolated from outbreaks in commercial poultry and form backyard poultry flocks in Pakistan. Infection, Genetics and Evolution. 2012;12:1010-1019\n'},{id:"B47",body:'Gershwin M, Beach R, Hurley L. The impact of nutritional factors on immune response. In: Nutrition and Immunity. New York, NY: Academic Press; 1985. pp. 1-7\n'},{id:"B48",body:'Lin YF, Chang SJ. Effect of dietary vitamin e on growth performance and immune response of breeder chickens. Asian Australian Journal of Animal Science. 2006;19:884-891\n'},{id:"B49",body:'Johri TS. Poultry Nutrition Research in India and its Perspective. India: Central Avian Research Institute; 2009\n'},{id:"B50",body:'Sanda ME, Ezeibe MCO, Anene BM. Effects of vitamins a, C and E and selenium on immune response of broilers to Newcastle (ND) vaccine. IOSR Journal of Agriculture and Veterinary Science. 2015;8(7):13-15. DOI: 10.9790/2380-08721315\n'},{id:"B51",body:'Cunha TJ. Nutrition and disease interaction. Feedstuffs. 1985;57(41):37-42\n'},{id:"B52",body:'Nockels CF, Odde KG, Crag AM. Vitamin E supplementation and stress affect tissue tocopherol content of beef heifers. Journal of Animal Science. 1996;74:672\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Aamir Sharif",address:"aamirsharifcheema@gmail.com",affiliation:'
Government Poultry Farm, Attock, Livestock and Dairy Development Department, Pakistan
Department of Clinical Sciences, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan, Pakistan
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Noeske",authors:[{id:"110737",title:"Dr.",name:"Jürgen",middleName:null,surname:"Noeske",fullName:"Jürgen Noeske",slug:"jurgen-noeske"}]},{id:"36958",title:"Social Determinants of Health in Deaf Communities",slug:"social-determinants-of-health-disparities-deaf-communities",signatures:"Scott R. Smith and Nancy P. Chin",authors:[{id:"105528",title:"Dr.",name:"Scott",middleName:null,surname:"Smith",fullName:"Scott Smith",slug:"scott-smith"},{id:"115286",title:"Prof.",name:"Nancy",middleName:null,surname:"Chin",fullName:"Nancy Chin",slug:"nancy-chin"}]},{id:"36959",title:"Anxiety and Emotional Discomfort in the School Environment: The Interplay of School Processes, Learning Strategies, and Children's Mental Health",slug:"anxiety-and-depression-in-the-school-environment-the-interplay-of-school-processes-learning-strateis",signatures:"L. Tramonte and J. D. Willms",authors:[{id:"117527",title:"Dr.",name:"Lucia",middleName:null,surname:"Tramonte",fullName:"Lucia Tramonte",slug:"lucia-tramonte"},{id:"119002",title:"Dr.",name:"Jon Douglas",middleName:null,surname:"Willms",fullName:"Jon Douglas Willms",slug:"jon-douglas-willms"}]},{id:"36960",title:"Re-Emergence of HIV Infection and Syphilis Among Men Who Have Sex with Men",slug:"re-emergence-of-hiv-infection-and-syphilis-among-men-who-have-sex-with-men",signatures:"Maria Antonella Di Benedetto, Nino Romano and Alberto Firenze",authors:[{id:"112350",title:"Prof.",name:"Alberto",middleName:null,surname:"Firenze",fullName:"Alberto Firenze",slug:"alberto-firenze"}]},{id:"36961",title:"Gun Violence in the United States: A Public Health Epidemic",slug:"gun-violence-in-the-united-states-a-public-health-epidemic",signatures:"Amy J. 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\n
1. Introduction
\n
In vitro fertilization (IVF) techniques enabled conception outside the body and led to the birth of the first child conceived in vitro in 1978 [1]. The first laboratory technique used for conception in vitro was “classic” IVF where a suspension of prepared sperm cells is added to oocytes surrounded by cumulus cells and fertilization occurs naturally. The most discouraging result of such assisted reproduction technology (ART) treatment was fertilization failure, occurring often with the male infertility factor or unexplained infertility. The development of a micromanipulation technique named intracytoplasmic sperm injection (ICSI) in 1990 [2] enabled new treatment possibilities for many couples. Bypassing initial steps in the process of natural fertilization, a single spermatozoon is inserted directly into the cytoplasm. Successful fertilization is thus also achieved with low sperm numbers, surgically retrieved sperm, or frozen sperm samples. ICSI was soon globally accepted as a reliable technique leading to successful fertilization, pregnancy, and healthy offspring. Although ICSI can overcome some fertilization problems, total fertilization failure (TFF) still occurs in some ICSI cycles. In some patients, this failure can repeat in several ART cycles. Some patients have extremely low fertilization rates, which consequently lowers their chances for successful treatment.
\n
Studies of etiology of fertilization failure after ICSI revealed that the predominant cause is oocyte activation failure [3, 4]. In humans, oocyte activation is the transition of the oocyte into a zygote where a series of intracellular calcium (Ca2+) oscillations following the fusion of the gametes play an essential role. Calcium ions are released from intracellular storage in the endoplasmic reticulum; free in the cytosol, they are intracellular messengers and act as modulators of processes in the early steps of fertilization and embryo development. In humans, oocyte activation thus describes a cascade of events that lead to completion of the meiosis, cortical granule exocytosis for prevention of polyspermy, formation of the male and female pronuclei and progression in the first embryonic cell cycle. Both sperm and oocyte defects can cause failed activation.
\n
Artificial oocyte activation (AOA) methods can be used in clinical practice in reproductive medicine in rare cases of TFF or low fertilization. AOA tries to reproduce elevations of calcium ion concentration in cytosol, which are necessary for triggering downstream processes in oocyte activation.
\n
\n
\n
2. Total fertilization failure (TFF) after ICSI
\n
Total fertilization failure after ICSI is complete lack of fertilization at the standard checking time of 17 ± 1 h post ICSI. This means that the obvious sign, female and male pronuclei, is not visible in any of the injected mature oocytes in the metaphase of meiosis II (MII) of the patient.
\n
According to data from the literature, complete fertilization failure occurs in: 2 [5], 1.3 [6], 3 [7], 3 [8], 5.6 [9], and 4.3% [10] of ICSI cycles.
\n
Complete fertilization failure after ICSI is directly correlated with the number of mature oocytes available [9], so the definition is needed. TFF is not surprising in cases of poor ovarian response, nonmotile spermatozoa, or poor sperm morphology. But even if we have a sufficient number of mature oocytes of normal morphology and sperm of good quality, TFF happens and can reoccur in subsequent cycles.
\n
Another problem that also lowers the chances for successful treatment of infertility is an extremely low fertilization rate.
\n
\n
2.1 Results of retrospective analysis of data from our center
\n
We analyzed all consecutive ICSI cycles in the period between years 2011 and 2016. Results are presented in Table 1. In this period, we performed 7474 ART cycles (IVF and ICSI) in our center. The majority of these cycles were stimulated with gonadotropins (recombinant FSH or highly purified human menopausal gonadotropin) with pituitary suppression using agonists or antagonists, followed by hCG administration for 36–37 h before ultrasound-guided follicle aspiration. Some of these cycles were natural cycles, as previously described in [11].
\n
\n
\n
\n
\n
\n
\n\n
\n
\n
Cycles with ≥3MII
\n
Cycles with <3MII
\n
Cycles with >0% and <30% fertilization (≥3MII)
\n
Cycles with >70% fertilization (≥3MII)
\n
\n\n\n
\n
N of all cycles
\n
3550
\n
983
\n
175
\n
1980
\n
\n
\n
N of TFF cycles (%)
\n
76 (2.14%)
\n
171 (17.4%)
\n
/
\n
/
\n
\n
\n
Woman age (years)
\n
35.62 ± 4.42
\n
37.26 ± 4.69
\n
34.70 ± 4.96
\n
34.14 ± 4.65
\n
\n
\n
Stimulation protocol
\n
\n
\n
• Natural cycles
\n
/
\n
35 (20.5%)
\n
/
\n
/
\n
\n
\n
• Long protocol with agonists GnRHa
\n
26 (34.2%)
\n
23 (13.5%)
\n
58 (33.1%)
\n
595 (30.6%)
\n
\n
\n
• Short protocol with antagonists antGnRH
\n
45 (59.2%)
\n
101 (59.1%)
\n
105 (60.0%)
\n
1297 (65.1%)
\n
\n
\n
• Other
\n
5
\n
12
\n
12
\n
88
\n
\n
\n
Duration of stimulation
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10.40 ± 1.95
\n
8.77 ± 4.85
\n
9.96 ± 1.76
\n
9.98 ± 1.8
\n
\n
\n
Gonadotropin dose (ampoules)
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32.80 ± 11.84
\n
31.53 ± 20.72
\n
28.86 ± 10.75
\n
27.34 ± 9.92
\n
\n
\n
N oocytes
\n
8.04 ± 6.10
\n
2.02 ± 2.46
\n
10.16 ± 5.4
\n
10.16 ± 5.95
\n
\n
\n
MII
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5.80 ± 4.13
\n
1.25 ± 0.44
\n
7.91 ± 4.41
\n
8.51 ± 5.07
\n
\n
\n
2PN
\n
0
\n
0
\n
1.35 ± 1.21
\n
7.37 ± 4.33
\n
\n
\n
1PN
\n
0.07 ± 0.25
\n
0.09 ±0.30
\n
0.16 ± 0.40
\n
0.12 ± 0.37
\n
\n
\n
3PN
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0.16 ± 0.49
\n
0.26 ± 1.11
\n
0.22 ± 0.64
\n
0.10 ± 0.35
\n
\n
\n
Damaged
\n
0.29 ± 0.82
\n
0.26 ± 1.11
\n
0.57 ± 1.06
\n
0.22 ± 0.55
\n
\n
\n
Male diagnosis
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\n
\n
\n
\n
\n
\n
• Normozoospermia (% of TFF cycles)
\n
15 (19.74%)
\n
61 (35.67%)
\n
31 (17.7%)
\n
371 (18.7%)
\n
\n
\n
• Krypto- and azoospermia (% of TFF cycles)
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18 (23.68%)
\n
17 (9.94%)
\n
45 (25.7%)
\n
214 (10.8%)
\n
\n
\n
ET
\n
0
\n
0
\n
1.04 ± 0.76
\n
1.57 ± 0.69
\n
\n
\n
Clinical pregnancy
\n
/
\n
/
\n
39/220 17.7%
\n
702/1822 38.5%
\n
\n
\n
Birth rate
\n
/
\n
/
\n
13.2%
\n
30.5%
\n
\n\n
Table 1.
Analysis of all consecutive ICSI cycles performed in our clinic in the period between years 2011 and 2016 (N = 4533); cycles with at least one mature oocyte in the metaphase stage of meiosis II (MII) are included. Data are presented in means ± SD or number of cases (percentage of all cases in a group).
\n
In this period, we performed 4533 ICSI cycles with at least one mature oocyte in the metaphase stage of meiosis II (MII) available. Complete fertilization failure (TFF) occurred in 247 (5.5%) of ICSI cycles.
\n
We compared standard characteristics of these cycles regarding the number of oocytes. There were 3550 cycles with 3 or more MII oocytes, TFF occurred in 76 among the (2.14%) cycles. There were 983 cycles with 1 or 2 MII oocytes available, TFF occurred in 171 among them (17.4%). A total of 35 of these TFF cycles were natural cycles.
\n
We also analyzed the characteristics of cycles with 3 or more MII oocytes and low fertilization; in doing so, we took into account cycles with more than 0% and less than 30% MII oocytes fertilized. There were 175 such cycles (3.9%).
\n
Woman’s age is greater in cycles with fewer oocytes, which can be explained with lower ovarian reserve in greater age. Regarding the stimulation protocol of the ART cycles, there were 35 natural cycles in the group with <3 MII oocytes. In our center, natural cycles are mainly performed in patients with extremely low ovarian response, where increasing gonadotropin dosage does not increase the chance to obtain more oocytes.
\n
In TFF cases where 3 or more MII oocytes are available, there is a higher proportion of severe male infertility cases (22.68%) compared to the cycles with less than 3 MII oocytes (9.94%). When there are more oocytes available, there is statistically less probability for TFF, and more cases of TFF are due to gamete defects. A similar proportion of low fertilization cycles are those with severe male infertility (25.7%). Severe male infertility is described as diagnosis of cryptozoospermia and azoospermia, where individual sperms have to be extracted from semen sediments or testis aspirates/biopsies.
\n
In cases where only one mature oocyte was available, total fertilization failure occurred more often (30.8%) than in those with more oocytes.
\n
In Figure 1, the correlation between the number of available mature oocytes and occurrence of TFF is presented. With more oocytes available, there is less probability for TFF.
\n
Figure 1.
Number of available oocytes and incidence of TFF. The proportion of ICSI cycles with total fertilization failure regarding the number of mature oocytes available; x = number of injected MII oocytes; y = % of cycles with TFF. 4533 ICSI cycles analysed.
\n
\n
\n
\n
3. Etiology of failed fertilization after ICSI
\n
Soon after implementation of the ICSI technique, some investigations of possible reasons for unsuccessful fertilization began. It was first speculated that perhaps the proportion of unfertilized oocytes arises from technical limitations of the method itself that cannot deliver the sperm in the cytoplasm, or ejection of the sperm from the cytoplasm occurs after injection. It was established that in only 7 [12], 16.7 [7], 10.6 [13], and 12.6% [14] of unfertilized oocytes after ICSI the sperm DNA was outside the oocytes.
\n
With different staining techniques, visualization of the chromatin, spindle, and other structures was possible, and this enabled a better understanding of at what stage unfertilized oocytes are (Table 2). It soon became evident that the majority of unfertilized oocytes are arrested in the metaphase of the meiosis II with different levels of sperm chromatin decondensation, which suggested that oocyte activation and sperm decondensation run independently [15]. In the majority of these oocytes, sperm chromatin is in a decondensed state, which indicates that protamines are usually successfully replaced by histones [14], so unsuccessful decondensation of sperm chromatin can be the underlying cause for only a relatively small proportion of unfertilized oocytes. Premature chromosome condensation (PCC) is a condition when sperm chromosomes are getting condensed in the cytoplasm of oocyte too early and the right synchronization between sperm and oocyte genetic material is compromised. Up to 33% of studied unfertilized oocytes had PCC [15], but it is difficult to conclude whether this indicates sperm- or oocyte-borne defect.
Giemsa: stain for adenine-thymine rich regions in DNA
\n
n = 82 NF MII
\n
93% oocytes having sperm in cytoplasm and MII chromosomes of the oocyte present; of these 51% SC, 41% intact SC, 8% premature chromosome condensation (PCC)
Chromomycin A3: binds to G-C rich DNA regions, does not bind to DNA coupled with protamines Propidium iodide: fluorescent DNA stain
\n
n = 93 NF MII
\n
74.8% metaphase MII oocytes; of these 63.6% decondensed SC, 23.4% condensed SC, and 13% no sperm in the cytoplasm. In majority of spermatozoa, successful replacement of protamines with histones took place.
\n
\n
\n
Rawe VY, Olmedo SB, Nodar FN, Doncel GD, Acosta AA, and Vitullo AD [16]
\n
Immunofluorescence analysis with immunoglobulins and monoclonal antibodies
\n
n = 150 NF MII
\n
13.3% oocytes with no sperm, 39.9% activation failure, 22.6% defects of pronuclear formation/migration, 13.3% arrest in metaphase of the 1st mitotic division
On the basis of the studies listed in Table 2, we can conclude that failed oocyte activation seems to be the predominant reason for fertilization failure. However, it is unclear whether the cause is sperm or oocyte defect, since proteins, organelles, and metabolic paths of both gametes are involved in the activation.
\n
Oocyte activation failure being the main problem was also confirmed by electron microscopy, where unreleased cortical granule at periphery, maternal chromosomes in the metaphase plate, and paternal intact or partially decondensed chromatin were found [3]. These are all signs of failed activation, but it is difficult to conclude on which level in the cascade there is a failure.
\n
Perhaps, in the future, genetic data will give us more information on the etiology of fertilization failure. An interesting case report where researchers investigated possible reasons for fertilization failure on genetic levels analyzed gene expression profiles in unfertilized oocytes of a patient with previous TFF history [17].
\n
\n
\n
4. Oocyte activation
\n
Oocyte activation is a downstream cascade triggered by sperm that causes progression of the oocyte from meiosis arrested in metaphase II toward its completion and beginning of embryonic development. It is a serial of biochemical reactions, organelle redistribution, changes in metabolism, transmembrane potentials, mRNA translation, gene transcription, and cytoskeletal rearrangements.
\n
The role of calcium in fertilization was established very early with a series of experiments on sea urchin eggs where the amount of bound and free calcium was measured in fertilized and nonfertilized eggs [18]. Later, calcium-specific light-emitting protein aequorin injected in fish oocytes enabled visualization of light flash after fusion of oocyte and sperm [19]. It soon became evident that calcium ions play an essential role in activation of the animal oocyte and that the frequencies and amplitudes of these elevations of calcium ions in cytoplasm are species-specific [20].
\n
The term “oocyte activation” probably evolved on the basis of these evident sudden changes that happen during the transition from oocyte to embryo. It describes not only calcium waves that occur but also other processes and morphological changes that happen during fertilization. Intracytoplasmic calcium elevation is essential for fertilization, but it is not always the sperm that triggers it. In some animal species such as fruit flies (Drosophila) the calcium wave occurs prior to oocyte-sperm fusion, during ovulation [21]. The focus of our text will be human oocyte activation, but since nonhuman biological material is usually more available or even easier to study, many data on fertilization come from studies on sea organisms such as starfish and sea urchins or different mammalian species. Early studies of the role of calcium in the process of fertilization and even use of ionophores are well documented in the review of Epel [22]. The source of an intracellular rise of calcium ion concentration can be external—calcium enters the cell by influx through calcium channels in the plasma membrane or can be released in cytoplasm from intracellular stores in the endoplasmic reticulum [23].
\n
But it is important to understand that the details vary a lot through the animal kingdom and that these differences can be the reason why the ICSI method can be successful in humans but not in other species. However, the animal studies are the foundation for the development of assisted reproduction techniques in human medicine.
\n
Early studies of fertilization in mammals are well reviewed by Miyazaki [24]; in sum, there is the first hyperpolarization of membrane potential as a result of a change in potassium conductivity across the plasma membrane. This coincides with an increase of free calcium in cytosol; there is no electrical block of polyspermy and a serial of intracytoplasmic rises of calcium concentration follow continuously (oscillations) at intervals of different frequencies and amplitudes, which depends on the species studied. Intracellular calcium first rises near the site of the sperm attachment and spreads like a wave over the entire egg [24]. The model of generating calcium spikes from intracellular stores in the endoplasmic reticulum was described by Igusa and Miyazaki [25]. The techniques used for revealing these processes were measurements with calcium-sensitive microelectrodes, the voltage-clamp technique, aequorin injections, injection of calcium ion chelators, and injection of different compounds that interact with the calcium-releasing system.
\n
The first study of calcium measurements at fertilization in human oocytes showed that the first rise in intracytoplasmic calcium concentration appears 20–35 min after adding sperm suspension in a chamber with oocytes; spikes appear every 10–35 min, with a single spike of amplitude up to 2.25 μM calcium concentration and duration of 100–120 s [26].
\n
Other researchers studied changes of membrane potential across the plasma membrane in human oocytes at fertilization and showed that the increase of potassium ion conductivity of the plasma membrane and outward current of ions, which causes hyperpolarization, is calcium dependent [27]. A study on bovine oocytes gave more information about the relationship between hyperpolarization of the plasma membrane potential and calcium release from intracellular stores and targeted calcium-activated potassium channels as membrane proteins involved in the process [28].
\n
Soon after introducing ICSI, it was of great interest to compare these responses with the classic IVF method, where events such as sperm capacitation and activation, acrosome reaction, and sperm-oocyte membrane fusion happen first. From the work of Tesarik et al. [29], we can see that when performing ICSI in human oocytes, the first intracytoplasmic rise of calcium ion concentration happens immediately; the peak is 10–15 s after penetration with the needle. Sperm then evokes intracellular calcium oscillations. They described that oscillations follow the lag period that lasts 4–12 h. Oscillations are in the form of spikes that last 20 s; the intervals between spikes are 1–5 min. The duration of the oscillatory phase is 30 min–1 h; at the end of the period, the amplitude of calcium spikes gets smaller.
\n
The proposed mechanism through which calcium oscillations are maintained is through the phosphoinositide signaling pathway, where inositol 1,4,5-trisphosphate (InsP3) is generated from phosphatidylinositol 4,5-bisphosphate (PIP2) [23]. The positive feedback cycle involving calcium-dependent InsP3 generation and InsP3-induced calcium release seem to be responsible for the oscillations [23]. The main protein is InsP3 receptor (InsP3R), a ligand-gated channel found in the membrane of the endoplasmic reticulum that allows calcium release from the ER [30].
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That calcium oscillations have a role in long-term embryonic events and provide more than merely a stimulus for meiotic resumption was shown in experiments with different activating agents and subsequent measurements of cell mass of the blastocyst [31].
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4.1 The role of free calcium ions in cytoplasm
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Calcium is the secondary messenger that regulates different events during fertilization, such as progression of the cell cycle from metaphase II arrest toward chromatid segregation, extrusion of the second polar body and completion of the second meiotic division, and cortical granule exocytosis [32]. The role of calcium in reproduction is preserved through evolution; it is important in plants and animals. Species-specific calcium signatures, like oscillations in mammals, have evolved, which are optimal for activation and development of a specific type of organism [33]. The variations in amplitude, duration, and frequency of oscillations over time are coordinated with the cell cycle, and experimentally changing them also affects development in the later stages when blastocyst forms [31]. Experiments with injecting calcium (Ca2+) chelators in the cytosol of frog eggs demonstrated the blockage of activation [34].
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Calcium rises in cytosol are converted in different cellular responses.
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4.1.1 Ca2+-dependent process of cortical granule exocytosis
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Cortical granule exocytosis enables polyspermy block by altering the zona pellucida with the content of the granule (proteases, peroxidases, and glycosaminoglycans) and prevent more sperms from fertilizing oocytes. The proposed model is that calcium stimulates Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) and myosin light-chain kinase (MLCK) that phosphorylate a vesicle targeting protein and myosin II to promote exocytosis [33]. It is a quick response; in mouse oocytes, exocytosis starts 15 min after exposure to capacitated sperm, and 30 min after insemination, 78% of cortical granules disappear from cytoplasm [35]. It is proposed that each calcium oscillation cycle moves cortical granule one step closer to the egg plasma membrane toward the fusion with the plasma membrane and exocytosis of the contents [33].
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4.1.2 Ca2+ is a trigger for cell cycle progression
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The completion of meiosis means that the extrusion of the chromatids in the second polar body enables the formation of haploid oocytes that can form a female pronucleus that will be able to combine genetic material with the male pronucleus.
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Meiosis is the ground of sexual reproduction where homologous chromosomes recombine—exchange genetic material through chiasmata and generate new genetic combinations that are unique to the offspring. Mammalian oocytes progress through meiosis very slowly; first, the cell cycle is arrested in the dictyate phase of prophase I during the fetal life of a girl and stays in this phase up to 40–50 years. During the menstrual cycle, the recruited oocytes in the ovary progress through the cell cycle under the influence of the hormones. But the meiosis is again arrested at the metaphase of the second meiotic division (metMII). Calcium oscillations at fertilization activate calmodulin-dependent protein kinase II (CaMKII) and switch on the anaphase-promoting complex/cyclosome (APC/C) that leads to securin and cyclin B1 degradation necessary for cell cycle progression and segregation of sister chromatids [33].
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Ca2+ also plays a role in pronuclear formation by decreasing MAP kinase (MAPK) activity responsible for nuclear envelope assembly [33]. Oscillations terminate with PN formation, and PLCζ localizes into PN [36]. The mechanism by which Ca2+ recruits maternal mRNA for translation and genome activation is not well understood at the moment. There are some data indicating that calcium oscillations and mRNA translation are coupled [37]. Not only in cytosol, calcium can also diffuse to the nucleus and control different cell functions by direct nuclear calcium signaling [38].
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4.2 Electrophysiology and fertilization
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Fertilization potential is a change in the membrane potential across the plasma membrane (PM) of the oocyte that is first observed after oocyte-sperm interaction. In many invertebrates, this is in the form of depolarization of the plasma membrane and is proposed to provide a fast block to polyspermy, described in some invertebrates and only a few vertebrates (such as frogs), but not present in mammals [39]. Lately, there have been some discussions about the nature of electrical block in preventing polyspermy [40]. The role of electrical events in the form of depolarization or hyperpolarization of the plasma membrane at fertilization remains unclear.
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In mammals, there is hyperpolarization of membrane potential as a result of change in potassium conductivity across the plasma membrane [24]. In human oocytes, outward current and long-lasting hyperpolarization of the plasma membrane were described [27]. The channels responsible for this hyperpolarization are calcium-activated potassium channels [41]. Species-specific differences in the channels involved in early electrical responses at fertilization are reviewed in [42].
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During oocyte maturation, the composition of the channels in the plasma membrane changes, as described in bovine oocytes [28]. The factors regulating the composition of channels in the plasma membrane, the conductance for different ions, depending on the specificity, gating, and sensitivity of the channels at different stages, are still unclear. The conditions during gamete maturation are very important, and we can imagine that diet and changes in metabolic pathways can affect the performance. It is not just cytoplasmic maturity of the oocyte that is important, but also maturity of the plasma membrane.
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The conditions in which gametes are matured are important; the diet and especially taking some medicines in this period can affect the infertility treatment outcome. There are some data from studies of calcium channel blockers used as therapy in various cardiovascular conditions. They affect the movement of free calcium ions across membranes, and dose-dependent reduction in sperm mobility and viability in vitro that can affect fertility treatment was demonstrated [43].
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4.3 Sperm factors
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Data from studies of fertilization pointed to a sperm component that has to trigger response in the form of calcium oscillations. But the exact component, its nature, and mechanism were long unknown.
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There were four main hypotheses, reviewed in [44]. The first one assumed that sperm delivers calcium to the oocyte that further stimulates release of calcium from intracellular stores. The conduit hypothesis assumed that sperm increases the permeability of the plasma membrane for calcium that enters the oocyte with influx from the surroundings. The contact hypothesis predicts that sperm interacts with a receptor on the plasma membrane that causes calcium release from intracellular stores. But success of the ICSI method revealed that there is no need for interaction of sperm and receptors in the plasma membrane for fertilization. The fourth is the sperm factor hypothesis that assumes that there is a component in the sperm cell delivered in cytosol with sperm and that this factor causes calcium release from intracellular stores.
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Experiments where soluble sperm extracts are injected into the oocyte coupled with different biochemical approaches enabled the search for unknown sperm factor and were in favor of the sperm factor hypothesis [45, 46].
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There were many candidates such as oscillin, a cytosolic sperm factor related to prokaryote glucosamine phosphate deaminase [47]. In nonmammalian species, PLCγ was identified [48] and the role of nitric oxide in fertilization was investigated [49]. In mammals post-acrosomal WW domain-binding protein (PAWP) was described, which is located in the post-acrosomal region of the sperm, from the stage of elongated spermatids onwards, that causes meiosis resumption and PN formation [50].
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4.3.1 PLCζ
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When it was demonstrated that sperm extracts were related to InsP3 concentrations in cell and PLC activity [51], phospholipases were under investigation. Genetic data from the testis’ cDNA library revealed some new isoform of PLC [23] and soon a novel sperm-specific phospholipase C, PLCζ was identified as a trigger of calcium oscillations in mouse eggs [52]. In the work of Saunders et al., it was experimentally demonstrated that PLCζ content in a single sperm evoked oscillations and normal embryonic development [52]. They also prepared PLCζ complementary RNA (cRNA) for injection into MII oocytes that triggered the same effect. When they removed PLCζ from sperm extracts, they no longer induced calcium oscillations.
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Important evidence that PLCζ is the necessary trigger for calcium oscillations comes also from the studies of Dpy19l2 knockout mice that have globozoospermic sperm phenotype and absence of or extremely reduced PLC ζ and no ability to trigger calcium oscillations [53]. But proof in the form of the knockout mouse model was missing. By using RNA interference technology that prevents translation of PLCζ mRNA and that reduces the amount of PLCζ protein in transgenic mouse sperm, altered calcium oscillation patterns, lower egg activation, and no transgenic offspring [54] were observed.
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A study where whole exome sequencing was performed in patients with previous TFF, homozygous missense mutation in PLCζ was established [55].
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PLCζ was identified in many mammalian and nonmammalian species [56, 57] and can act across species. But there are differences in solubility of PLCζ in cytosol that can contribute to differences between species. It is proven in the mouse oocyte activation test (MOAT) that human PLCζ exhibits greater response in mouse oocytes than mouse PLCζ.
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The amount of PLCζ measured in a single mouse sperm cell is in the same range as the amount required to cause oscillations experimentally [52]. This can explain why altered frequency of oscillations was established when more than one sperm fertilized an oocyte [58]. PLCζ has to diffuse through cytosol to trigger spatiotemporal response in the form of a calcium wave that spreads from the point of sperm entry to the other pole.
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Recently, the knockout mouse model was prepared using CRISPR/Cas9 gene editing [59] and revealed interesting facts: PLCζ-null mouse males have normal spermatogenesis and normal sperm parameters (motility, capacitation, and acrosome reaction) but their sperm cannot elicit calcium oscillations after ICSI. Still, some oocytes can undergo activation in abnormal form or even develop to blastocyst stage. But mating knockout males with normal females shows that they can still produce offspring without PLCζ as a physiological trigger. Males are not infertile, rather subfertile, so there is possibility that apart from PLCζ, there is a second calcium releasing factor delivered to oocyte by sperm, perhaps an alternative that is used only when PLCζ is missing.
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Calcium oscillations are normal physiological stimuli for oocyte activation but from parthenogenetic activation at ICSI and from the use of artificial oocyte activation techniques we already know that they are not always necessary to activate oocytes. They can be bypassed on some levels.
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There are still many facts about calcium oscillations triggering that are not well understood. The proposed mechanism of activation is reviewed in [23] and represented in a schematic diagram (Figure 2): PLCζ diffuses from the sperm head into egg cytosol and hydrolyses the PIP2 (phosphatidylinositol 4,5-bisphosphate) in the membrane of the vesicle compartment into products InsP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol). InsP3 binds to the receptor InsP3R on the endoplasmic reticulum membrane. The conformation of the channel is changed and it becomes permeable for Ca2+ ions that are released from intracellular storage in the endoplasmic reticulum into cytosol. Oscillations are generated through a positive feedback loop.
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Figure 2.
Schematic diagram of the proposed model of sperm triggered oocyte activation at fertilization in mammals: after the fusion of sperm and oocyte plasma membrane PLCζ diffuses from sperm into oocyte cytosol. Vesicles baring PIP2 are present in cytosol and PLCζ hydrolyzes PIP2 into products DAG and InsP3. InsP3 binds to the InsP3R present in the membrane of ER. InsP3R is a ligand-gated Ca2+ release channel and Ca2+ is released from intracellular stores in ER into the cytosol. In mammals, repetitive Ca2+ oscillations occur, and several rises of calcium concentration in cytosol take place. Ca2+ ions play an essential role in oocyte activation. They enable block of polyspermy by chemically altering zona pellucida with the content of cortical granules that are released in the perivitelline space. Ca2+ ions enable cell cycle progression—resumption of meiosis II. Ca2+-dependent inactivation of factors that hold cell cycle in arrested state takes place, by degradation of cyclinB1 and securin and MPF inactivation of cell cycle eventually progresses. Ca2+ ions play a role in recruitment of mRNAs and affect their translation. Ca2+ can diffuse in the nucleus and play a role in embryonic gene activation. Ca2+ oscillations terminate when female pronucleus is formed and PLCζ relocalizes in the pronucleus. PLCζ—phospholipase C zeta, PIP2—phosphatidylinositol 4,5-bisphosphate, InsP3—inositol 1,4,5-trisphosphate, DAG—diacylglycerol, InsP3R—inositol 1,4,5-trisphosphate receptor, Ca2+—calcium ions, ZP—zona pellucida (the glycoprotein envelope surrounding mammalian oocyte), PV—perivitelline space (space between ZP and plasma membrane of oocyte), PM—plasma membrane, cg—cortical granules, and PN—pronucleus.
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In a series of experiments on mouse oocytes injected with RNA encoding PLCζ and tagged with a fluorescent protein, it was established that at the time when calcium oscillations terminate and pronucleus is formed, PLCζ protein translocates from the cytosol to the pronucleus [36]. Authors also demonstrated that it is again released in the cytosol in the first mitotic division of an embryo at the time of nuclear envelope breakdown and observed also in the second mitotic division. This suggests the possible role of calcium oscillations not only in oocyte activation but also in early embryonic development.
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All together there is a lot of accumulating evidence that points toward PLCζ as a trigger of oocyte activation cascade in mammals. Soon the idea of using recombinant PLCζ in clinical practice emerged that will be discussed later among other methods for artificial oocyte activation. But still there are many data missing that are needed to fully understand oocyte activation.
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4.3.2 Other sperm-related factors that affect oocyte activation
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Spermatozoon has to go through many changes in order to be able to fertilize an oocyte naturally. First, the mechanism of chemotaxis between the gametes plays an important role; capacitation is the process of altering the sperm plasma membrane so that it becomes more permanent for calcium ions, then changes in sperm movements in the form of hyperactivation help to bring the spermatozoon closer to the oocyte. Finally, at acrosome reaction the content of acrosomes (enzymes) facilitates the fusion between the plasma membrane of the oocyte and spermatozoon so that the paternal genetic material can enter the oocyte. Sperm also delivers a centriole into the oocyte that duplicates and forms centrosome, a microtubule-organizing center responsible for mitotic divisions in a growing embryo. ICSI bypasses many of these events and enables fertilization and successful development, but there are still sperm factors other than PLCζ that can contribute to failure of oocyte activation.
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Successful sperm chromatin decondensation is a necessary condition for fertilization. The chromatin of the spermatozoon is uniquely packaged in such a way that histones become replaced by protamines during the spermatogenesis. Protamines provide more structural stability but after the entry of the spermatozoon into the oocyte the chromatin of the spermatozoon must be uncoiled and protamines must be replaced by histones. Proteins and other factors in the cytosol of an oocyte play a role in the correct decondensation of male genetic material.
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Mitosis-promoting factor (MPF) in the cytosol of an oocyte can cause premature chromosome condensation (PCC), but perhaps it is not only an oocyte-related problem. It was established that protamine-deficient sperm seems to be related to a higher proportion of PCC independent of oocyte cytoplasmic maturity [60, 61]. The cell cycle of spermatozoa is related to chromatin status and protamine-histone remodeling must be synchronized with the oocyte.
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4.4 Oocyte factors
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If PLCζ depletion in sperm is a good candidate for explaining fertilization failure of male origin, less is known about different oocyte defects that cause unsuccessful activation. It is obvious that oocyte maturation is crucial and competent oocytes of good quality with all the necessary elements in the downstream cascade must be available. In the process of oocyte maturation, not only the elements responsible for generating calcium oscillations must develop but also all other elements such as those responsible for exocytosis of cortical granules, the necessary actin cortical cytoskeleton, and energy resources must be available.
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The direct proof of oocyte-borne defects is the results of the mouse oocyte activation test (MOAT) that will be discussed in detail later. It is a heterologous model where mouse oocytes are fertilized with the patient’s sperm. Successful fertilization of mouse oocytes points toward oocyte defects that are the underlying cause of previous fertilization failure in ART treatments in a specific couple.
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4.4.1 Organelle distribution
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Studies of the ultrastructure of unfertilized oocytes with transmission or scanning electron microscopy revealed differences in oocyte ultrastructure that can reflect different stages in oocyte maturation [62].
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Cortical granule migration toward the plasma membrane is an important step in cytoplasmic maturation and it is a cytoskeleton-dependent process [63].
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Some studies have investigated the relationship between mitochondrial function and fertilization. Unfertilized oocytes exhibit a higher proportion of mtDNA deletions that may contribute to their malfunction and ATP production [64]. As the early embryo requires a lot of energy, it is important that during oocyte maturation a sufficient number and functionality of the mitochondria are prepared.
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Reorganization of the endoplasmic reticulum (ER) during maturation seems to play an important role in oocyte competence to generate calcium oscillations. Visualization of the ER in mouse oocytes revealed that in prophase I (in the germinal vesicle stage) the ER is in the form of a fine network with patch-like accumulations in the inner cytoplasm. After the resumption of meiosis, the ER accumulates in the form of a dense ring in the center of the oocyte, around the meiotic apparatus; later the ER rings move together with a meiotic spindle toward the oocyte cortex [65]. In oocytes in metaphase II, the ER ring transforms into clusters in the cortical region; in the central cytoplasm the reticular form is present [65]. These researchers also showed that these relocalizations happen independently from meiotic progression and that microtubules, dyneins, and actins are responsible for the movements.
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During oocyte maturation, the Ins3R receptors responsible for calcium release from the endoplasmic reticulum achieve their functionality. In a mouse model, it was demonstrated that increase in IP3R1 sensitivity is underpinned, at least in part, by increases in calcium concentrations within the endoplasmic reticulum and receptor phosphorylation but not by changes in IP3R1 distribution [66].
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Distribution of vesicles with PIP2 is also important. PLCζ diffuses from the sperm head into egg cytosol and acts on PIP2 that is present in the membrane of small vesicles in the cytoplasm. Defects or deficits of PIP2 or vesicles could contribute to fertilization failure [30].
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4.4.2 Cytoplasmic maturation
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Evaluation of oocyte maturity relies on the presence of the first polar body, but it is difficult to evaluate in daily IVF laboratory practice whether the oocyte cytoplasm is mature.
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Cytoplasmic maturity is an important factor determining the ability of the oocyte to activate. During oocyte cytoplasmic maturation, the mechanisms responsible for sperm-induced calcium oscillations and oocyte activation develop and are reviewed in [67].
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It was experimentally shown in LT/Sv mouse strain (that has abnormal oocyte nuclear maturation arrested at metaphase I) that the ability of these oocytes to be activated by sperm develops gradually during cytoplasmic maturation independent of nuclear maturation [68].
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Oocyte cytoplasmic maturity also plays a role in decondensation of the sperm genetic material that is tightly packed with protamines. Oocyte immaturity is correlated to the occurrence of premature chromosome condensation (PCC) of the male pronucleus [69].
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Evaluation of cytoplasmic maturity with immunocytochemical methods revealed that metaphase plate rearrangements are more frequent in oocytes showing immaturity [70]. Another study investigated abnormal maturation in patients with a high proportion of immature oocytes [71].
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It is obvious that the conditions in which oocytes mature are important and beside patient-related factors there are also cycle-specific factors that have an impact on oocyte maturity, quality, and fertilization. Little is known about the cellular mechanisms of how diet, medicament uptake, or tobacco/alcohol intake affect oocyte quality. In a review of [72], the environmental impact on oocyte function through mitochondrial level is discussed.
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5. Artificial oocyte activation (AOA)
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Artificial oocyte activation methods try to induce oocyte activation by using physiological properties of the gametes and in this way interfere in different levels of the cascade of events during fertilization. In general, they try to alleviate intracellular calcium concentration and mimic oscillations. As we are well aware by now that there is big species-specific variability in the mechanisms of oocyte activation, it is not surprising that different AOA methods can be successful in one species, but not in another.
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By influencing gamete physiological properties such as electrical excitability and plasma membrane conductivity, the aim is to increase intracytoplasmic calcium concentrations and mimic the frequency and amplitude of the oscillations.
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Basically, there are three types of AOA methods: electrical, chemical, and mechanical.
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5.1 Electrical methods
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By applying direct electrical current within a Petri dish with oocytes, the electrical field stimulates charged proteins to move toward the plasma membrane, and by this, the number of pores in the plasma membrane increases [30]. Calcium conductivity increases, and more calcium enters the oocyte from the surroundings. There is only one large calcium concentration increase.
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In the prospective randomized study of [73], an electrical pulse in a special chamber with electrodes 30 minutes after ICSI in 0.3 M glucose drops was used to activate oocytes, and a small increase in the fertilization rate after ICSI was achieved. Successful pregnancy and birth were achieved and reported in the case report [74].
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In a study with round spermatid injection coupled with electrostimulation, the electrical pulse triggered not only a single calcium concentration increase, but a series of calcium spikes after spermatid injection [75].
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5.2 Chemical methods
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Chemical activation is the most commonly used method. Oocytes are exposed to chemical agents that lead to an increase in intracellular calcium concentration in the oocyte. Some agents, such as calcium ionophores cause a single, prolonged calcium transient, while others cause multiple oscillations.
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5.2.1 Ionophores
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Calcium ionophores, such as ionomycin, A23187 (calcimycin), and gm508 are molecules soluble in lipids, synthesized by microorganisms; today several synthetic compounds are known. They can transport ions across lipid bilayers. They increase membrane permeability for Ca2+ ions, thus allowing calcium influx in the oocyte from the surrounding medium and intracytoplasmic rise of calcium concentration. It has been recently established that intracytoplasmic rise of calcium concentration in human and mouse oocytes is not only the consequence of the influx from the surroundings but also from intracellular stores, since this rise appears also in calcium-free medium. However, they are not able to induce calcium oscillations typical for mammalian species but a single rise. Different protocols are described in the literature, regarding different concentrations used, and intervals of ionophore exposition [76, 77, 78, 79].
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They are used in cases of repeating TFF or low fertilization, oligoteratoasthenospermia cases, globozoospermia, in vitro maturation of oocytes (IVM), unexplained female infertility, and low ovarian reserve, with patients with Kartagener’s syndrome with no response on theophylline, at primary ciliary dyskinesia. They are the most widely used chemical agents for artificial oocyte activation.
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5.2.2 Strontium chloride (SrCl2)
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It is reported as very efficient in mice and induces not only single calcium concentration elevation, but oscillations [80]. The mechanism by which it induces oscillations is not fully understood.
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A study that investigated efficacy of SrCl2 in human oocytes showed significantly increased fertilization rates, when compared with conventional ICSI or calcium ionophore treatment [81].
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5.2.3 PLCζ
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Soon after the discovery of the role of PLCζ as a trigger of oocyte activation, the ideas of using the protein as an artificial activator emerged. The synthesis of the first recombinant human PLCζ protein was published [82]; when injected into mouse oocytes, calcium oscillations were evoked that closely resembled those initiated by the sperm after fertilization. Later, a study where human recombinant PLCζ was used on human and mouse oocytes was published [83] describing dose-dependent manner of calcium oscillations. These authors also showed that by injecting recombinant human PLCζ the next day in oocytes that failed to fertilize after ICSI, five of eight oocytes were rescued.
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Earlier, it was established that PLCζ complementary RNA (cRNA) injection in MII oocytes also triggered oscillations [52] with a time lag that enables protein to synthesize.
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The commercial use of recombinant human PLCζ still has to be validated in terms of safety.
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5.2.4 Ethanol
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In veterinary medicine, ethanol is often used for parthenogenetic oocyte activation. Parthenogenesis is development of an embryo from an unfertilized oocyte, naturally occurring in invertebrates or even some vertebrates. By inhibiting the second polar body extrusion, diploid parthenotes with two maternal genomes can be created and embryos can develop normally for several days, but later die. In several species, artificial parthenogenetic activation was described to be caused by ethanol [84].
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5.3 Mechanical methods
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Some data from the literature suggest that the modified ICSI technique can give better fertilization in patients with a history of TFF or low fertilization [85, 86]. Vigorous aspiration of cytoplasm and a different position of the pipette tip when ejecting sperm in the oocyte is supposed to increase calcium levels during injection and enable better contact of sperm with intracellular storage of calcium.
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6. Diagnostic tools for assessing sperm- or oocyte-dependent activation defects
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A proper diagnostic procedure is very important prior to the decision to use artificial oocyte activation, and oocyte or sperm donation is a reasonable treatment option for some couples [87].
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There are several diagnostic methods available, but not always accessible to all clinics since legislation can prohibit the use of heterologous human-animal models.
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The mouse oocyte activation test (MOAT) is a heterologous ICSI model where mouse oocytes are fertilized with the patient’s sperm [78]. As a negative control, mouse oocytes are injected with the medium and as a positive control, they are injected with donor sperm with proven fertilizing ability. It allows discrimination between sperm- and oocyte-borne causes for fertilization failure. According to the ratio of fertilized mouse oocytes, three groups are described: MOAT1 indicating sperm-borne defects, MOAT2 fertilization failure of unknown origin, MOAT3 sperm defects are excluded indicating oocyte defects.
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In some patients from groups MOAT2 or MOAT3, capacity to activate mouse oocytes is demonstrated but later ICSI-AOA results in TFF. In these cases, assessment of calcium oscillations can give better answers as to whether the underlying reason is the presence of human sperm activation deficiencies or oocyte-related activation deficiency. Mouse oocyte Ca2+ analysis (M-OCA) or even more sensitive human oocyte Ca2+ analysis (H-OCA) can be performed before using AOA [88]. In the M-OCA test, the patient’s sperm is used and frequency patterns of calcium oscillations are analyzed. H-OCA yields higher sensitivity than M-OCA to detect the presence of human sperm activation deficiencies. It helps detect cases with suspected oocyte-related activation deficiency.
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7. Success rates of AOA
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The systematic review and meta-analysis of RCTs that compared ICSI-AOA and conventional ICSI first established that there is insufficient evidence available from RCTs to judge the efficacy and safety of ICSI-AOA for couples with previous fertilization failure [89]. A total of 14 articles were assessed and 9 included in meta-analysis. It cannot be concluded that the outcomes are improved using ICSI followed by artificial oocyte activation compared with conventional ICSI. The fertilization rate, cleavage rate, and likelihood of blastocyst formation seem to improve according to some studies, but it is difficult to make a general conclusion.
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Recently, important evidence appeared that the conditions in which activation takes place are very important for the success rate and can vary a lot. Varying concentrations of both ionomycin and calcium ions in culture media used during AOA can have significant effects on calcium release and further embryonic developmental potential .
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8. Safety of AOA methods
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Although AOA methods have been proven efficient to overcome some cases of TFF, the concern around using them in clinical practice is quite big. By artificially increasing intracellular calcium levels we interfere with cellular mechanisms that normally would not occur. Nature has regulatory mechanisms to eliminate errors and when we force events that would not happen spontaneously it is always important to verify all possible negative effects of such procedures.
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The number of children born after AOA is relatively small for statistical analysis, but there are accumulating data on the safety of these methods. The study from Ghent analyzed neonatal and neurodevelopmental outcomes of 21 children born after cycles with AOA [90]. For all tests and questionnaires, the mean outcomes lay within the expected ranges, but since the number of studied cases is small, the authors state that AOA should still be performed only in selected couples. In another study, 79 children born following AOA-ICSI and 89 born by ICSI were compared in terms of intrauterine fetal death, preterm delivery, birth weight, growth rate, hospitalization in neonatal intensive care units, abnormal behavior according to age, and the physical and mental health of children born and no significant differences were found [91].
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In a study, genetic content of donated oocytes in metaphase II artificially activated with calcium-ionophore was analyzed. By using array comparative genomic hybridization, single-nucleotide polymorphism genotyping and maternal haplotyping chromosome segregation errors in meiosis II were not increased compared to the control group [92].
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There are concerns about the effects of AOA on gene expression and later embryonic development coming from animal studies [33, 93]. In the case of the use of SrCl2 for AOA, data in mice show that birth weight of male pups is reduced [80].
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9. Conclusions
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The problem of failed fertilization is a big burden for patients and clinicians and the pressure to help these patients is enormous. Today, ART methods are generally easily accessible and patients’ expectations are very high. In Europe alone, there have been 1,308,289 children born from IVF treatments between the years 1997 and 2013 according to data collected in European IVF monitoring [94]. Global data collection on IVF is a difficult task, but there are reports that in a three-year period, more than a million babies are born worldwide [95]. Despite the great success of ART, there are always some patients facing fertilization failure and the emotional burden of inability to achieve pregnancy is great for these couples. For successful fertilization, sperm must activate a quiescent oocyte to complete meiosis and progress toward embryonic development characterized with repeated mitotic divisions. Oocyte activation is a complex cascade of intracellular processes. Sperm or oocyte abnormalities can contribute to activation failure. In clinical practice, there is a need for safe methods of artificial oocyte activation based on the physiological properties of the gametes that closely imitate calcium oscillations triggered naturally by sperm.
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Conflict of interest
The authors confirm that there are no known “conflicts of interest” associated with this publication.
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Notes/thanks/other declarations
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The publication is a part of research program P3-0327 and research project J3-7177 funded by the Slovenian Research Agency.
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\n',keywords:"oocyte activation, total fertilization failure (TFF), calcium oscillations, artificial oocyte activation (AOA), gamete maturation, ion channels, ion currents, calcium signaling, meiosis, intracytoplasmic sperm injection (ICSI), PLCζ, calcium ionophores",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65172.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65172.xml",downloadPdfUrl:"/chapter/pdf-download/65172",previewPdfUrl:"/chapter/pdf-preview/65172",totalDownloads:1709,totalViews:4,totalCrossrefCites:1,dateSubmitted:"May 1st 2018",dateReviewed:"December 11th 2018",datePrePublished:"February 7th 2019",datePublished:"August 28th 2019",dateFinished:"January 12th 2019",readingETA:"0",abstract:"Despite successful treatment of infertility with assisted reproductive technology (ART), total fertilization failure (TFF) after in vitro fertilization (IVF) and even after intracytoplasmic sperm injection (ICSI) still occurs. In the current chapter, the incidence and etiology of TFF after ICSI are described. The literature on physiology of oocyte activation, electrical properties of gametes’ membranes, and ion currents is reviewed. Calcium oscillations play an essential role in fertilization, and calcium ions act as secondary messengers in different metabolic pathways and cellular processes during oocyte activation. The contribution of oocyte- and sperm-related causes of fertilization failure is discussed. Many studies on the physiology of fertilization in mammals have shown that oocyte activation is triggered by the sperm factor. Methods for artificial oocyte activation (AOA) try to bypass fertilization failure by influencing physiological processes that are crucial for successful fertilization. Activation can be induced with the use of electrical, mechanical, or chemical stimuli that elevate intracellular concentrations of calcium ions. Different AOA methods and their success and safety are presented.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65172",risUrl:"/chapter/ris/65172",signatures:"Nina Hojnik and Borut Kovačič",book:{id:"6977",type:"book",title:"Embryology",subtitle:"Theory and Practice",fullTitle:"Embryology - Theory and Practice",slug:"embryology-theory-and-practice",publishedDate:"August 28th 2019",bookSignature:"Bin Wu and Huai L. Feng",coverURL:"https://cdn.intechopen.com/books/images_new/6977.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-306-3",printIsbn:"978-1-78985-305-6",pdfIsbn:"978-1-78985-639-2",isAvailableForWebshopOrdering:!0,editors:[{id:"108807",title:"Ph.D.",name:"Bin",middleName:null,surname:"Wu",slug:"bin-wu",fullName:"Bin Wu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"257108",title:"Prof.",name:"Borut",middleName:null,surname:"Kovačič",fullName:"Borut Kovačič",slug:"borut-kovacic",email:"borut.kov63@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"257110",title:"MSc.",name:"Nina",middleName:null,surname:"Hojnik",fullName:"Nina Hojnik",slug:"nina-hojnik",email:"hojnina@ukc-mb.si",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Total fertilization failure (TFF) after ICSI",level:"1"},{id:"sec_2_2",title:"2.1 Results of retrospective analysis of data from our center",level:"2"},{id:"sec_4",title:"3. Etiology of failed fertilization after ICSI",level:"1"},{id:"sec_5",title:"4. Oocyte activation",level:"1"},{id:"sec_5_2",title:"4.1 The role of free calcium ions in cytoplasm",level:"2"},{id:"sec_5_3",title:"4.1.1 Ca2+-dependent process of cortical granule exocytosis",level:"3"},{id:"sec_6_3",title:"4.1.2 Ca2+ is a trigger for cell cycle progression",level:"3"},{id:"sec_8_2",title:"4.2 Electrophysiology and fertilization",level:"2"},{id:"sec_9_2",title:"4.3 Sperm factors",level:"2"},{id:"sec_9_3",title:"4.3.1 PLCζ",level:"3"},{id:"sec_10_3",title:"4.3.2 Other sperm-related factors that affect oocyte activation",level:"3"},{id:"sec_12_2",title:"4.4 Oocyte factors",level:"2"},{id:"sec_12_3",title:"4.4.1 Organelle distribution",level:"3"},{id:"sec_13_3",title:"4.4.2 Cytoplasmic maturation",level:"3"},{id:"sec_16",title:"5. Artificial oocyte activation (AOA)",level:"1"},{id:"sec_16_2",title:"5.1 Electrical methods",level:"2"},{id:"sec_17_2",title:"5.2 Chemical methods",level:"2"},{id:"sec_17_3",title:"5.2.1 Ionophores",level:"3"},{id:"sec_18_3",title:"5.2.2 Strontium chloride (SrCl2)",level:"3"},{id:"sec_19_3",title:"5.2.3 PLCζ",level:"3"},{id:"sec_20_3",title:"5.2.4 Ethanol",level:"3"},{id:"sec_22_2",title:"5.3 Mechanical methods",level:"2"},{id:"sec_24",title:"6. Diagnostic tools for assessing sperm- or oocyte-dependent activation defects",level:"1"},{id:"sec_25",title:"7. Success rates of AOA",level:"1"},{id:"sec_26",title:"8. Safety of AOA methods",level:"1"},{id:"sec_27",title:"9. Conclusions",level:"1"},{id:"sec_31",title:"Conflict of interest",level:"1"},{id:"sec_28",title:"Notes/thanks/other declarations",level:"1"}],chapterReferences:[{id:"B1",body:'Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. 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International committee for monitoring assisted reproductive technologies world report: Assisted reproductive technology 2008, 2009 and 2010. Human Reproduction. 2016;31(7):1588-1609\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Nina Hojnik",address:"hojnina@ukc-mb.si",affiliation:'
Department of Reproductive Medicine and Gynecological Endocrinology, University Medical Centre Maribor, Maribor, Slovenia
Department of Reproductive Medicine and Gynecological Endocrinology, University Medical Centre Maribor, Maribor, Slovenia
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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). 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