RESUMEN
The recent centennial anniversary of R.E. Montgomery's seminal published description of "a form of swine fever" disease transmitted from wild African pigs to European domestic pigs is a call to action to accelerate African Swine Fever (ASF) vaccine research and development. ASF modified live virus (MLV) first-generation gene deleted vaccine candidates currently offer the most promise to meet international and national guidelines and regulatory requirements for veterinary product licensure and market authorization. A major, rate-limiting impediment to the acceleration of current as well as future vaccine candidates into regulatory development is the absence of internationally harmonized standards for assessing vaccine purity, potency, safety, and efficacy. This review summarizes the asymmetrical landscape of peer-reviewed published literature on ASF MLV vaccine approaches and lead candidates, primarily studied to date in the research laboratory in proof-of-concept or early feasibility clinical safety and efficacy studies. Initial recommendations are offered toward eventual consensus of international harmonized guidelines and standards for ASF MLV vaccine purity, potency, safety, and efficacy. To help ensure the successful regulatory development and approval of ASF MLV first generation vaccines by national regulatory associated government agencies, the World Organisation for Animal Health (WOAH) establishment and publication of harmonized international guidelines is paramount.
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Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Vacunas Virales , Animales , Virus de la Fiebre Porcina Africana/genética , Sus scrofa , Porcinos , Vacunas Atenuadas , Guías como AsuntoRESUMEN
New solutions are necessary for the singular global health security threat formed by endemic, epidemic, and emerging/re-emerging zoonoses, coupled with epizootic and enzootic transboundary animal diseases (TADs). This One Health issue is related to the daily interactions between wildlife, domesticated and indigenous livestock, and humans primarily associated with global trade, transboundary co-movement of humans and diverse livestock/livestock products, and agriculture production intensification and penetration into previously uninhabited areas. The World Health Organization defines Risk Group 3 (RG-3) and RG-4 pathogens as mainly viruses but also bacteria that serve as the foundation for approximately 60% of emerging infectious diseases that are zoonoses. The World Organisation for Animal Health defines trade-notifiable TADs, and subsets of these are zoonotic. Livestock vaccination policies mainly focus on TADs that are promulgated by the United Nations Food and Agriculture Organization and government agriculture agencies. The development, licensure, and product manufacturing of next-generation molecular-based RG-3 and RG-4 veterinary vaccines largely ignored by the global animal health biopharmaceutical sector can have an important positive impact on food security and One Health. There have been sharp increases in the global demand for livestock meat and milk products, especially in low- and middle-income countries in Africa and Asia. This relatively recent market driver-coupled with scientific advances in human EID and zoonotic disease vaccine platform technologies and increases in the number of high (US biosafety level 3 agriculture) and maximum (US animal biosafety level 4) biocontainment facilities with supporting workforce capabilities-offers new investment opportunities to the animal health biopharmaceutical sector. Moreover, a growing number of One Health public-private partnerships have moved the net present value calculus in favor of the financial feasibility of RG-3 and RG-4 veterinary vaccine product development and licensure. This article highlights the challenges and opportunities in the use of high and maximum biocontainment facilities in developing and licensing RG-3 and RG-4 veterinary vaccines that are safe and effective against epizootic and enzootic TADs and zoonotic diseases.
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Enfermedades de los Animales , Enfermedades Transmisibles Emergentes , Vacunas , Enfermedades de los Animales/epidemiología , Enfermedades de los Animales/prevención & control , Animales , Enfermedades Transmisibles Emergentes/epidemiología , Ganado , Zoonosis/prevención & controlRESUMEN
To prepare foot-and-mouth disease (FMD) recombinant vaccines in response to newly emerging FMD virus (FMDV) field strains, we evaluated Modified Vaccinia virus Ankara-Bavarian Nordic (MVA-BN®) as an FMD vaccine vector platform. The MVA-BN vector has the capacity to carry and express numerous foreign genes and thereby has the potential to encode antigens from multiple FMDV strains. Moreover, this vector has an extensive safety record in humans. All MVA-BN-FMD constructs expressed the FMDV A24 Cruzeiro P1 capsid polyprotein as antigen and the FMDV 3C protease required for processing of the polyprotein. Because the FMDV wild-type 3C protease is detrimental to mammalian cells, one of four FMDV 3C protease variants were utilized: wild-type, or one of three previously reported mutants intended to dampen protease activity (C142T, C142L) or to increase specificity and thereby reduce adverse effects (L127P). These 3C coding sequences were expressed under the control of different promoters selected to reduce 3C protease expression. Four MVA-BN-FMD constructs were evaluated in vitro for acceptable vector stability, FMDV P1 polyprotein expression, processing, and the potential for vaccine scale-up production. Two MVA-BN FMD constructs met the in vitro selection criteria to qualify for clinical studies: MVA-mBN360B (carrying a C142T mutant 3C protease and an HIV frameshift for reduced expression) and MVA-mBN386B (carrying a L127P mutant 3C protease). Both vaccines were safe in cattle and elicited low to moderate serum neutralization titers to FMDV following multiple dose administrations. Following FMDV homologous challenge, both vaccines conferred 100% protection against clinical FMD and viremia using single dose or prime-boost immunization regimens. The MVA-BN FMD vaccine platform was capable of differentiating infected from vaccinated animals (DIVA). The demonstration of the successful application of MVA-BN as an FMD vaccine vector provides a platform for further FMD vaccine development against more epidemiologically relevant FMDV strains.
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Virus de la Fiebre Aftosa/inmunología , Fiebre Aftosa/prevención & control , Vacunación/métodos , Vacunas Virales/administración & dosificación , Animales , Bovinos , Enfermedades de los Bovinos/inmunología , Enfermedades de los Bovinos/prevención & control , Enfermedades de los Bovinos/virología , Línea Celular , Fiebre Aftosa/inmunología , Células HeLa , Humanos , Serogrupo , Vacunación/veterinaria , Vacunas de ADN , Vacunas Sintéticas , Vacunas Virales/inmunología , Viremia/prevención & controlRESUMEN
Classical Swine Fever Virus (CSFV) causes classical swine fever, a highly contagious hemorrhagic fever affecting both feral and domesticated pigs. Outbreaks of CSF in Europe, Asia, Africa and South America had significant adverse impacts on animal health, food security and the pig industry. The disease is generally contained by prevention of exposure through import restrictions (e.g. banning import of live pigs and pork products), localized vaccination programmes and culling of infected or at-risk animals, often at very high cost. Current CSFV-modified live virus vaccines are protective, but do not allow differentiation of infected from vaccinated animals (DIVA), a critical aspect of disease surveillance programmes. Alternatively, first-generation subunit vaccines using the viral protein E2 allow for use of DIVA diagnostic tests, but are slow to induce a protective response, provide limited prevention of vertical transmission and may fail to block viral shedding. CSFV E2 subunit vaccines from a baculovirus/insect cell system have been developed for several vaccination campaigns in Europe and Asia. However, this expression system is considered expensive for a veterinary vaccine and is not ideal for wide-spread deployment. To address the issues of scalability, cost of production and immunogenicity, we have employed an Agrobacterium-mediated transient expression platform in Nicotiana benthamiana and formulated the purified antigen in novel oil-in-water emulsion adjuvants. We report the manufacturing of adjuvanted, plant-made CSFV E2 subunit vaccine. The vaccine provided complete protection in challenged pigs, even after single-dose vaccination, which was accompanied by strong virus neutralization antibody responses.
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Anticuerpos Antivirales/inmunología , Virus de la Fiebre Porcina Clásica/inmunología , Peste Porcina Clásica/prevención & control , Vacunación/veterinaria , Proteínas del Envoltorio Viral/inmunología , Vacunas Virales/inmunología , Adyuvantes Inmunológicos , Animales , Peste Porcina Clásica/virología , Virus de la Fiebre Porcina Clásica/genética , Femenino , Glicoproteínas/genética , Glicoproteínas/inmunología , Porcinos , Nicotiana/genética , Nicotiana/metabolismo , Vacunas de Subunidad/inmunología , Proteínas del Envoltorio Viral/genéticaRESUMEN
We investigated the serotype- and topotype versatility of a replication-deficient human adenovirus serotype 5 vectored foot-and-mouth disease (FMD) vaccine platform (AdtFMD). Sixteen AdtFMD recombinant subunit monovalent vaccines targeting twelve distinct FMD virus (FMDV) serotype/topotypes in FMD Regional Pools I-VII were constructed. The AdtA24 serotype conditionally licensed vaccine served as the basis for vaccine design and target dose for cattle clinical trials. Several vaccines contained an additional RGD motif genetic insertion in the adenovector fiber knob, and/or a full-length 2B gene insertion in the FMDV P1 gene cassette. In 13 of the 22 efficacy studies conducted, naïve control and AdtFMD vaccinated cattle were challenged intradermolingually at 2â¯weeks post-vaccination using a FMDV strain homologous to the AdtFMD vaccine strain. Each of the 16 AdtFMD vaccines were immunogenic based on the presence of homologous neutralizing antibodies in the serum of approximately 90% of total vaccinates (nâ¯=â¯375) on the day of challenge. Importantly, for 75% of vaccines tested, the effective dose that conferred 100% protection against clinical FMD was identical to or in some cases lower than, the minimum protective dose for the conditionally licensed AdtA24 vaccine formulated with ENABL® adjuvant. Results also confirmed the capability of the AdtFMD vaccine platform to differentiate infected from vaccinated animals (DIVA) across the five FMDV serotypes evaluated. Collectively, this comprehensive set of FMD cattle vaccine dose ranging studies highlights the serotype- and topotype versatility of the AdtFMD vaccine platform for further development, licensure, and application in FMD outbreak control and disease eradication efforts.
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Enfermedades de los Bovinos/prevención & control , Fiebre Aftosa/prevención & control , Vacunación/veterinaria , Vacunas Virales/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Bovinos , Relación Dosis-Respuesta a Droga , Virus de la Fiebre Aftosa , Vectores Genéticos , Serogrupo , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/uso terapéutico , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/uso terapéutico , Vacunas Virales/uso terapéuticoRESUMEN
BACKGROUND: A direct contact transmission challenge model was used to simulate natural foot-and-mouth disease virus (FMDV) spread from FMDV A24/Cruzeiro/BRA/55 infected 'seeder' steers to naïve or vaccinated steers previously immunized with a replication-deficient human adenovirus-vectored FMDV A24/Cruzeiro/BRA/55 capsid-based subunit vaccine (AdtA24). In two independent vaccine efficacy trials, AdtA24 was administered once intramuscularly in the neck 7 days prior to contact with FMDV A24/Cruzeiro/BRA/55-infected seeder steers. RESULTS: In Efficacy Study 1, we evaluated three doses of AdtA24 to estimate the 50%/90% bovine protective dose (BPD50/90) for prevention of clinical FMD. In vaccinated, contact-challenged steers, the BPD50/90 was 3.1 × 1010 / 5.5 × 1010 AdtA24 particles formulated without adjuvant. In Efficacy Study 2, steers vaccinated with 5 × 1010 AdtA24 particles, exposed to FMDV A24/Cruzeiro/BRA/55-infected seeder steers, did not develop clinical FMD or transmit FMDV to other vaccinated or naïve, non-vaccinated steers. In contrast, naïve, non-vaccinated steers that were subsequently exposed to FMDV A24/Cruzeiro/BRA/55-infected seeder steers developed clinical FMD and transmitted FMDV by contact to additional naïve, non-vaccinated steers. The AdtA24 vaccine differentiated infected from vaccinated animals (DIVA) because no antibodies to FMDV nonstructural proteins were detected prior to FMDV exposure. CONCLUSIONS: A single dose of the AdtA24 non-adjuvanted vaccine conferred protection against clinical FMD at 7 days post-vaccination following direct contact transmission from FMDV-infected, naïve, non-vaccinated steers. The AdtA24 vaccine was effective in preventing FMDV transmission from homologous challenged, contact-exposed, AdtA24-vaccinated, protected steers to co-mingled, susceptible steers, suggesting that the vaccine may be beneficial in reducing both the magnitude and duration of a FMDV outbreak in a commercial cattle production setting.
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Enfermedades de los Bovinos/prevención & control , Fiebre Aftosa/prevención & control , Vacunas Virales/inmunología , Adenovirus Humanos/genética , Animales , Anticuerpos Antivirales/sangre , Proteínas de la Cápside/genética , Bovinos , Enfermedades de los Bovinos/inmunología , Enfermedades de los Bovinos/virología , Fiebre Aftosa/inmunología , Fiebre Aftosa/virología , Virus de la Fiebre Aftosa/inmunología , Masculino , Serogrupo , Vacunación , Vacunas de Subunidad/inmunología , Proteínas no Estructurales Virales/inmunologíaRESUMEN
The highly contagious foot-and-mouth disease virus (FMDV) afflicts cloven-hoofed animals, resulting in significant costs because of loss of trade and recovery from disease. We developed a sensitive, specific, and rapid competitive ELISA (cELISA) to detect serum antibodies to FMDV. The cELISA utilized a monoclonal blocking antibody specific for a highly conserved FMDV nonstructural 3B epitope, a recombinant mutant FMDV 3ABC coating protein, and optimized format variables including serum incubation for 90 min at 20-25°C. Samples from 16 animals experimentally infected with one FMDV serotype (A, O, Asia, or SAT-1) demonstrated early detection capacity beginning 7 d post-inoculation. All samples from 55 vesicular stomatitis virus antibody-positive cattle and 44 samples from cloven-hoofed animals affected by non-FMD vesicular diseases were negative in the cELISA, demonstrating 100% analytical specificity. The diagnostic sensitivity was 100% against sera from 128 cattle infected with isolates of all FMDV serotypes, emphasizing serotype-agnostic results. Diagnostic specificities of U.S. cattle ( n = 1135) and swine ( n = 207) sera were 99.4% and 100%, respectively. High repeatability and reproducibility were demonstrated with 3.1% coefficient of variation in percent inhibition data and 100% agreement using 2 kit lots and 400 negative control serum samples, with no difference between bench and biosafety cabinet operation. Negative results from vaccinated, uninfected cattle, pig, and sheep sera confirmed the DIVA (differentiate infected from vaccinated animals) capability. This rapid (<3 h), select agent-free assay with high sensitivity and specificity, DIVA capability, and room temperature processing capability will serve as a useful tool in FMDV surveillance, emergency preparedness, response, and outbreak recovery programs.
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Anticuerpos Antivirales/sangre , Ensayo de Inmunoadsorción Enzimática/veterinaria , Virus de la Fiebre Aftosa/aislamiento & purificación , Fiebre Aftosa/diagnóstico , Proteínas no Estructurales Virales/aislamiento & purificación , Animales , Bovinos , Enfermedades de los Bovinos/diagnóstico , Enfermedades de los Bovinos/virología , Ensayo de Inmunoadsorción Enzimática/métodos , Epítopos/inmunología , Fiebre Aftosa/virología , Ovinos , Enfermedades de las Ovejas/diagnóstico , Enfermedades de las Ovejas/virología , Porcinos , Enfermedades de los Porcinos/diagnóstico , Enfermedades de los Porcinos/virologíaRESUMEN
There are links among agriculture and zoonotic diseases, transboundary diseases in domesticated and wild animals, climate patterns, and human population migrations. A natural or intentionally occurring high-consequence infectious disease ("biothreat") often has no geographic boundaries and has the potential to result in disease epidemics in humans, animals, or both. Although significant strides have been made globally in preparing for a natural or intentional introduction of an emerging and/or zoonotic disease, much remains to be accomplished. Enhancing animal health and well-being is a vital component to enable a sustainable, safe, and nutritious food supply for global food economies. This article explores the biothreat environment, its One Health interrelationship, and the significance and role of US agriculture in One Health. We provide an overview of the US Emergency Medical Countermeasure Enterprise (EMCE) and current state of veterinary and zoonotic medical countermeasures portfolio management in the US government, veterinary biologic industry, not-for-profit groups, and public-private partnerships. The highest zoonotic and epizootic threats to the US livestock industry are briefly reviewed, and currently available veterinary medical countermeasures are presented. Lastly, important gaps and priorities are identified, followed by specific recommendations to address these gaps.
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Agricultura/organización & administración , Salud Global , Salud Única/normas , Política Pública , Asociación entre el Sector Público-Privado/organización & administración , Agricultura/métodos , Enfermedades de los Animales , Animales , Animales Salvajes , Países en Desarrollo , Abastecimiento de Alimentos/normas , Humanos , Ganado , Salud Única/tendencias , Salud Pública , Estados Unidos , Zoonosis/prevención & control , Zoonosis/transmisiónRESUMEN
A foot-and-mouth disease (FMD) recombinant subunit vaccine formulated with a lipid/polymer adjuvant was evaluated in two vaccine efficacy challenge studies in steers. The vaccine active ingredient is a replication-deficient human adenovirus serotype 5 vector encoding the FMD virus (FMDV) A24/Cruzeiro/BRA/55 capsid (AdtA24). In the first study, AdtA24 formulated in ENABL® adjuvant was compared to a fourfold higher dose of AdtA24 without adjuvant. Steers vaccinated with AdtA24â¯+â¯ENABL® adjuvant developed a significantly higher virus neutralizing test (VNT) antibody titer and an improved clinical response following FMDV A24/Cruzeiro/BRA/55 intradermal lingual challenge at 14â¯days post-vaccination (dpv) than steers vaccinated with the active ingredient alone. In the second study, vaccination with AdtA24 formulated in ENABL® at the same dose used in the first study, followed by FMDV A24/Cruzeiro/BRA/55 challenge on 7 or 14 dpv, prevented clinical FMD in all steers and conferred 90% protection against viremia. In addition, post-challenge FMDV titers in nasal samples from vaccinated steers compared to unvaccinated steers were significantly reduced. In both studies, none of the AdtA24 vaccinated steers developed antibodies to the FMDV non-structural proteins prior to challenge with FMDV, indicative of the capacity to differentiate infected from vaccinated animals (DIVA). These results demonstrate that administration of AdtA24 formulated in ENABL® adjuvant lowered the protective dose and prevented clinical FMD following exposure of vaccinated steers to virulent FMDV at 7 or 14 dpv.
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Adenovirus Humanos/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Enfermedades de los Bovinos/prevención & control , Virus de la Fiebre Aftosa/inmunología , Fiebre Aftosa/prevención & control , Potencia de la Vacuna , Vacunas Virales/inmunología , Adenovirus Humanos/genética , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Bovinos , Virus de la Fiebre Aftosa/genética , Vectores Genéticos , Humanos , Serogrupo , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Vacunas Virales/administración & dosificación , Viremia/inmunologíaRESUMEN
The safety and efficacy of an experimental, replication-deficient, human adenovirus-vectored foot-and-mouth disease virus (FMDV) serotype A24 Cruzeiro capsid-based subunit vaccine (AdtA24) was examined in eight independent cattle studies. AdtA24 non-adjuvanted vaccine was administered intramuscularly to a total of 150 steers in doses ranging from approximately 1.0×10(8) to 2.1×10(11) particle units per animal. No detectable local or systemic reactions were observed after vaccination. At 7 days post-vaccination (dpv), vaccinated and control animals were challenged with FMDV serotype A24 Cruzeiro via the intradermal lingual route. Vaccine efficacy was measured by FMDV A24 serum neutralizing titers and by protection from clinical disease and viremia after challenge. The results of eight studies demonstrated a strong correlation between AdtA24 vaccine dose and protection from clinical disease (R(2)=0.97) and viremia (R(2)=0.98). There was also a strong correlation between FMDV A24 neutralization titers on day of challenge and protection from clinical disease (R(2)=0.99). Vaccination with AdtA24 enabled differentiation of infected from vaccinated animals (DIVA) as demonstrated by the absence of antibodies to the FMDV nonstructural proteins in vaccinates prior to challenge. Lack of AdtA24 vaccine shedding after vaccination was indicated by the absence of neutralizing antibody titers to both the adenovector and FMDV A24 Cruzeiro in control animals after co-mingling with vaccinated cattle for three to four weeks. In summary, a non-adjuvanted AdtA24 experimental vaccine was shown to be safe, immunogenic, consistently protected cattle at 7 dpv against direct, homologous FMDV challenge, and enabled differentiation of infected from vaccinated cattle prior to challenge.
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Adenoviridae , Enfermedades de los Bovinos/prevención & control , Fiebre Aftosa/prevención & control , Vacunas Virales/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Proteínas de la Cápside/inmunología , Bovinos , Enfermedades de los Bovinos/virología , Virus de la Fiebre Aftosa , Masculino , Pruebas de Neutralización , Serogrupo , Vacunas de Subunidad/inmunología , Proteínas no Estructurales Virales/inmunología , Esparcimiento de VirusRESUMEN
Immunological memory responses to intracellular protozoa and extracellular helminths govern host resistance and susceptibility to reinfection. Humans and livestock living in parasitic disease endemic regions face continuous exposure from a very early age that often leads to asymptomatic chronic infection over their entire lifespan. Fundamental immunological studies suggest that the generation of T-cell memory is driven by tightly coordinated innate and adaptive cellular immune responses rapidly triggered following initial host infection. A key distinguishing feature of immune memory maintenance between the majority of parasitic diseases and most bacterial or viral diseases is long-term antigen persistence. Consequently, functional parasite immune memory is in a continuous, dynamic flux between activation and deactivation producing functional parasite killing or functional memory cell death. In this sense, T-cell immune memory can be regarded as "memory illusion." Furthermore, due to the finite capacity of memory lymphocytes to proliferate, continuous parasite antigen stimulation may exceed a threshold level at some point in the chronically infected host. This may result in suboptimal effector immune memory leading to host susceptibility to reinfection, or immune dysregulation yielding disease reactivation or immune pathology. The goal of this review is to highlight, through numerous examples, what is currently known about T-cell immune memory to parasites and to provide compelling hypotheses on the survival and maintenance of parasite "memory illusion." These novel concepts are discussed in the context of rationale parasite vaccine design strategies.
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Interacciones Huésped-Parásitos/inmunología , Memoria Inmunológica/inmunología , Enfermedades Parasitarias/inmunología , Animales , Antígenos de Protozoos/inmunología , Apicomplexa/inmunología , Apicomplexa/patogenicidad , Humanos , Infecciones por Protozoos/inmunología , VacunasRESUMEN
Most mammalian immune systems and parasites have co-evolved over the millennia, interacting within a common environment and communicating through a common language. This language is comprised of copious dialects in which a variety of host innate and acquired immune pathways actively interact with a multitude of parasite-specific survival strategies. Nonetheless, a simplified language is likely present since the same basic molecular and cellular mechanisms are associated with resistance or susceptibility to parasite infection. Protective immunity against protozoa within the phylum Apicomplexa (e.g. Cryptosporidia, Eimeria, Neospora, Plasmodia and Toxoplasma) is generally CD4+ T cell-dependent and elicited along the IL-12/IFN-gamma/iNOS effector axis. This simplified language can be decoded in part by significant advances in understanding naïve T cell activation, differentiation and generation of immunologic memory. Vaccine adjuvants and new immunisation strategies for generation of more potent immunity can also be viewed through this common language lens. The aim of this paper is to summarise recently published fundamental immunology studies, their relevance through examples in specific coccidian-host immune dialects, and how this simplified language can be used for the more rationale design of parasite vaccine control strategies.