Process Development of Sj-p80: A Low-Cost Transmission-Blocking Veterinary Vaccine for Asiatic Schistosomiasis.

Asiatic schistosomiasis caused by Schistosoma japonicum is a neglected tropical disease resulting in significant morbidity to both humans and animals - particularly bovines - in endemic areas. Infection with this parasite leads to less healthy herds, causing problems in communities which rely on bovines for farming, milk and meat production. Additionally, excretion of parasite eggs in feces perpetuates the life cycle and can lead to human infection. We endeavored to develop a minimally purified, inexpensive, and effective vaccine based on the 80 kDa large subunit of the calcium activated neutral protease (calpain) from S. japonicum (Sj-p80). Here we describe the production of veterinary vaccine-grade Sj-p80 at four levels of purity and demonstrate in a pilot study that minimally purified antigen provides protection against infection in mice when paired with a low-cost veterinary adjuvant, Montanide™ ISA61 VG. Preliminary data demonstrate that the vaccine is immunogenic with robust antibody titers following immunization, and vaccination resulted in a reduction of parasite eggs being deposited in the liver (23.4-51.4%) and intestines (1.9-55.1%) depending on antigen purity as well as reducing the ability of these eggs to hatch into miracidia by up to 31.6%. We therefore present Sj-p80 as a candidate vaccine antigen for Asiatic schistosomiasis which is now primed for continued development and testing in bovines in endemic areas. A successful bovine vaccine could play a major role in reducing pathogen transmission to humans by interrupting the parasitic life cycle and improving quality of life for people living in endemic countries.

Are Eimeria Genetically Diverse, and Does It Matter?

Eimeria pose a risk to all livestock species as a cause of coccidiosis, reducing productivity and compromising animal welfare. Pressure to reduce drug use in the food chain makes the development of cost-effective vaccines against Eimeria essential. For novel vaccines to be successful, understanding genetic and antigenic diversity in field populations is key. Eimeria species that infect chickens are most significant, with Eimeria tenella among the best studied and most economically important. Genome-wide single nucleotide polymorphism (SNP)-based haplotyping has been used to determine population structure, genotype distribution, and potential for cross-fertilization between E. tenella strains. Here, we discuss recent developments in our understanding of diversity for Eimeria in relation to its specialized life cycle, distribution across the globe, and the challenges posed to vaccine development.

Successful vaccines for naturally occurring protozoal diseases of animals should guide human vaccine research. A review of protozoal vaccines and their designs.

Effective vaccines are available for many protozoal diseases of animals, including vaccines for zoonotic pathogens and for several species of vector-transmitted apicomplexan haemoparasites. In comparison with human diseases, vaccine development for animals has practical advantages such as the ability to perform experiments in the natural host, the option to manufacture some vaccines in vivo, and lower safety requirements. Although it is proper for human vaccines to be held to higher standards, the enduring lack of vaccines for human protozoal diseases is difficult to reconcile with the comparatively immense amount of research funding. Common tactical problems of human protozoal vaccine research include reliance upon adapted rather than natural animal disease models, and an overwhelming emphasis on novel approaches that are usually attempted in replacement of rather than for improvement upon the types of designs used in effective veterinary vaccines. Currently, all effective protozoal vaccines for animals are predicated upon the ability to grow protozoal organisms. Because human protozoal vaccines need to be as effective as animal vaccines, researchers should benefit from a comparison of existing veterinary products and leading experimental vaccine designs. With this in mind, protozoal vaccines are here reviewed.

East Coast fever immunisation field trial in crossbred dairy cattle in Hanang and Handeni districts in northern Tanzania.

East Coast fever (ECF) causes considerable mortality and production losses in the Tanzania smallholder dairy sector and limits the introduction of improved dairy breeds in areas where the disease is present. The infection and treatment method (ITM) was adopted by smallholder dairy farms for ECF immunisation in Hanang and Handeni districts of Tanzania. This study recorded incidence rates for ECF and other tick-borne diseases (TBDs) for ECF-immunised and non-immunised cattle between 1997 and 2000. Approximately 80% of smallholder households from both sites (n = 167) participated in this longitudinal study, with immunisations carried out at the request of the livestock owners. Efficacy of ITM for preventing ECF cases in these crossbred dairy cattle was estimated at 97.6%, while that for preventing ECF deaths was 97.9%. One percent of the cattle developed clinical ECF as a result of immunisation. Since ECF immunisation permits a reduction in acaricide use, an increase in other TBDs is a potential concern. Sixty-three percent of farmers continued to use the same acaricide after immunisation, with 80% of these reducing the frequency of applications. Overall, 78% of farmers increased the acaricide application interval after immunisation beyond that recommended by the manufacturer, resulting in annual savings in the region of USD 4.77 per animal. No statistical difference was observed between the immunised and non-immunised animals in the incidence of non-ECF TBDs. However, immunised animals that succumbed to these diseases showed fewer case fatalities. ITM would therefore appear to be a suitable method for ECF control in Tanzania's smallholder dairy sector.

Ranking control options for tropical theileriosis in at-risk dairy cattle in Tunisia, using benefit-cost analysis.

An economic evaluation of various control programmes against Theileria annulata infection was conducted on a sample of 49 Tunisian dairy farms where clinical cases of tropical theileriosis had been recorded during the summer. Indicators of morbidity and the prevalence of infection, as well as production and demographic indicators (recorded in the present survey ortaken from secondary sources), were used to rank the potential costs and benefits of various control programmes for tropical theileriosis over a time horizon of 15 years. Three options were considered, i.e. vaccination with a local attenuated cell-line vaccine; partial barn upgrading, based on first roughcasting then smoothing all the walls of the animal premises (inner and outer surfaces); and applying acaricides to control the vector tick population on the cattle. The most important loss from this disease, representing between 22% and 38% of the overall losses, is the loss in milk yield from carriers of T. annulata. Upgrading barns produced the highest mean benefit-cost ratio (1.62 to 3.71), while the ratios for vaccination and acaricides ranged from 0.20 to 1.19 and 0.32 to 0.88, respectively. However, the benefit-cost ratio of vaccination increased (from 1.65 to 5.41), when the costs due to carrier state infection, which vaccination does not prevent, were ignored. Upgrading barns is a sustainable eradication policy against tropical theileriosis, based on a single investment, and is environmentally friendly. This control option should be encouraged by national Veterinary Authorities in regions where tropical theileriosis is transmitted by a domestic endophilic tick.

The potential economic value of a Trypanosoma cruzi (Chagas disease) vaccine in Latin America.

BACKGROUND: Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), is the leading etiology of non-ischemic heart disease worldwide, with Latin America bearing the majority of the burden. This substantial burden and the limitations of current interventions have motivated efforts to develop a vaccine against T. cruzi. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a decision analytic Markov computer simulation model to assess the potential economic value of a T. cruzi vaccine in Latin America from the societal perspective. Each simulation run calculated the incremental cost-effectiveness ratio (ICER), or the cost per disability-adjusted life year (DALY) avoided, of vaccination. Sensitivity analyses evaluated the impact of varying key model parameters such as vaccine cost (range: $0.50-$200), vaccine efficacy (range: 25%-75%), the cost of acute-phase drug treatment (range: $10-$150 to account for variations in acute-phase treatment regimens), and risk of infection (range: 1%-20%). Additional analyses determined the incremental cost of vaccinating an individual and the cost per averted congestive heart failure case. Vaccination was considered highly cost-effective when the ICER was ≤1 times the GDP/capita, still cost-effective when the ICER was between 1 and 3 times the GDP/capita, and not cost-effective when the ICER was >3 times the GDP/capita. Our results showed vaccination to be very cost-effective and often economically dominant (i.e., saving costs as well providing health benefits) for a wide range of scenarios, e.g., even when risk of infection was as low as 1% and vaccine efficacy was as low as 25%. Vaccinating an individual could likely provide net cost savings that rise substantially as risk of infection or vaccine efficacy increase. CONCLUSIONS/SIGNIFICANCE: Results indicate that a T. cruzi vaccine could provide substantial economic benefit, depending on the cost of the vaccine, and support continued efforts to develop a human vaccine.

3rd Global Vaccine Congress.

Singapore was the location of the 3rd Global Vaccine Congress on 4-6 October 2009, and it provided a suitable place for sharing a range of developments, concepts and challenges associated with vaccines. One of the major goals of this meeting was to present a broad and balanced program of research, development, production, clinical testing and delivery of vaccines to people living in different parts of the world. This report contains an overview of recent developments in the vaccine field against a range of infections and disease situations that were presented during the meeting. The highlights included challenges to the current constraints on the timely and cost-effective development of vaccines and a focus on the H1N1 influenza pandemic concerns. The meeting also generated presentations that challenged the regulatory and political status quo in order to expand global access to vaccines and facilitate speedier and more cost-effective development of new vaccines.

Prizes and parasites: incentive models for addressing Chagas disease.

Recent advances in immunology have provided a foundation of knowledge to understand many of the intricacies involved in manipulating the human response to fight parasitic infections, and a great deal has been learned from malaria vaccine efforts regarding strategies for developing parasite vaccines. There has been some encouraging progress in the development of a Chagas vaccine in animal models. A prize fund for Chagas could be instrumental in ensuring that these efforts are translated into products that benefit patients.

Neospora caninum--how close are we to development of an efficacious vaccine that prevents abortion in cattle?

Neospora caninum is a protozoan parasite that causes abortion in cattle around the world. Although the clinical signs of disease in both dogs and cattle have now been recognised for over 20years, treatment and control options are still limited, despite the availability of a commercial vaccine in some countries of the world. The case for an efficacious vaccine has not been convincingly waged by farmers, veterinarians and other members of the agricultural and rural communities. In recent times, however, economic modelling has been used to estimate the industry losses due to Neospora-associated abortion, providing, in turn, the business case for forms of control for this parasite, including the development of vaccines. In this review, we document progress in all areas of the vaccine development pipeline, including live, killed and recombinant forms and the animal models available for vaccine evaluation. In addition, we summarise the main outcomes on the economics of Neospora control and suggest that the current boom in the global dairy industry increases the specific need for a vaccine against N. caninum-associated abortion.

Live immunization against East Coast fever--current status.

The infection-and-treatment method (ITM) for immunization of cattle against East Coast fever has historically been used only on a limited scale because of logistical and policy constraints. Recent large-scale deployment among pastoralists in Tanzania has stimulated demand. Concurrently, a suite of molecular tools, developed from the Theileria parva genome, has enabled improved quality control of the immunizing stabilate and post-immunization monitoring of the efficacy and biological impact of ITM in the field. This article outlines the current status of ITM immunization in the field, with associated developments in the molecular epidemiology of T. parva.

The transfer of East Coast fever immunisation to veterinary paraprofessionals in Zambia.

In eastern Zambia, immunisation by 'infection and treatment' is the main method used to control East Coast fever, an acute and lethal cattle disease. This service, which requires a stringent cold chain, used to be free of charge. When a minimal user fee was introduced, attendance dropped drastically. Consequently, this complex immunisation programme was transferred to veterinary paraprofessionals working on their own account, with the aim of boosting a more sustainable distribution of vaccine. Paraprofessionals were provided with a motorbike and the required specific equipment, but fuel and drugs were at their expenses. The paraprofessionals recovered their costs, with a profit margin, by charging the cattle owners for immunisation. The reasons for the successful transfer of immunisation to paraprofessionals (despite the maintenance of a fee) are attributed mainly to the absence of information asymmetry between the paraprofessional and the livestock owner, the appreciable level of effort of the paraprofessionals and the verifiable outcome of the service provided.

Review on the experience with live attenuated vaccines against tropical theileriosis in Tunisia: considerations for the present and implications for the future.

The choice of a vaccine candidate against tropical theileriosis was based on key epidemiological considerations inherent to the main target endemic situation in Tunisia. One of the attenuated cell lines was retained as a vaccine candidate on the basis of small-scale trials testing the intrinsic safety aspects of the vaccine for the targeted animal categories in the dominant endemic situation where it will be used. The vaccine efficacy was confirmed in pilot vaccination campaigns using fresh culture and thawed cryopreserved vaccine doses delivered to the field using a new delivery system not requiring a cold chain. The potential benefit of the live attenuated Tunisian vaccine was evaluated using simple economical models.

Epidemiological aspects and economic impact of bovine theileriosis (East Coast fever) and its control: a preliminary assessment with special reference to Kibaha district, Tanzania.

A cross-sectional study based on clinical examination, inspection of herd health records and a questionnaire was designed to determine the epidemiology, economics and potential impact of immunisation against theileriosis in Tanzania. The results showed annual theileriosis costs to be US$ 205.40 per head, whereas the introduction of immunisation reduced this by 40-68% depending on the post immunisation dipping strategy adopted. Morbidity risk due to theileriosis was 0.048 in immunised and 0.235 in non-immunised cattle, and the difference was significant (chi(2)=66.7; P=0.000). The questionnaire results indicated that immunised cattle had a significantly (chi(2)=6; P=0.015) higher risk of anaplasmosis compared with non-immunised cattle, whereas the risk of bovine babesiosis did not differ significantly (chi(2)=0.06; P=0.807) between the two groups. Mortality risk due to anaplasmosis was 0.046 in immunised and 0.018 in non-immunised cattle and this difference was statistically significant (chi(2)=4.48; P=0.043). The theileriosis mortality risk was 0.203 in the non-immunised cattle, while the risk was 0.009 in the immunised cattle and these differences were also significant (chi(2)=103; P=0.000). It was concluded that farmers who have immunised their cattle may cautiously cut down acaricide application by 50% for extensively grazed herds and by 75% for zero grazed animals depending on the level of tick challenge at the herd level.

The efficacy and economic benefits of Supercox, a live anticoccidial vaccine in a commercial trial in broiler chickens in China.

The efficacy and economic benefits of Supercox, a live anticoccidial vaccine were examined and compared with an anticoccidial drug in a trial in broiler chickens under modern commercial conditions in China. In total, 40,660 chickens were used in the present study, half of which were vaccinated with the Supercox vaccine comprising a precocious line of Eimeria tenella and non-attenuated lines of Eimeria maxima and Eimeria acervulina, and the other half were medicated with Diclazuril delivered as feed additive at the dosage of 1mg/kg of feed. The vaccine was administered orally to 7-day-old chickens. No clinical diseases were diagnosed in any of the vaccinated birds. However, clinical coccidiosis occurred in a large proportion of medicated control birds and these chickens had to be treated with anticoccidial drugs (Diclazuril and Toltrazuril). Comparison of production performance between vaccinated birds and medicated control birds revealed that the vaccine Supercox performed better than anticoccidial drugs in terms of mortalities, costs and overall economic benefits (profits). These findings demonstrated that the use of the Supercox vaccine could control clinical coccidiosis in broilers and achieve production performance superior to that using anticoccidial drugs, particularly where drug resistance might result in failure to control clinical diseases.

Infection of calves with Theileria annulata in Tunisia: Economic analysis and evaluation of the potential benefit of vaccination.

A field study aiming to estimate the costs of tropical theileriosis was carried out in an endemic region of the North of Tunisia. Three farms were monitored for two successive summer seasons. A total number of 56 calves and 12 sentinel cows were monitored. Calves were ranked into four groups: non infected animals, diseased animals with clinical tropical theileriosis, sub-clinical Theileria annulata infected animals with anaemia and sub-clinical T. annulata infected animals without anaemia. The total costs due to disease and infection were estimated to be 15,115.058 TD (Euro 9388.20). A high proportion of these costs (50.81%) is accounted for by asymptomatic infection. Sub-clinical infections with anaemia showed the highest losses in live weight, while disease cases (prevalence 42.86%) are responsible for 23.64% of the losses with death as the most important element. A cost-benefit analysis of vaccination using a Tunisian attenuated cell line vaccine was also undertaken. Considering that the vaccine would cost 5 TD (Euro 3.10), the cost-benefit ratio of vaccination is 23.7. Sensitivity analysis of the vaccination costs shows that the indifference decision point is around 118 TD (Euro 73.29).

Economics of theileriosis control in Zambia.

For an economic analysis of theileriosis control, we adopted the total economic cost (TEC) method, which calculates the sum of output losses from tick damage, theileriosis mortality and morbidity, and expenditures for treatment or prevention of the disease. At farm level, the TEC can be minimized by a specific combination of vector control and/or immunization and an acceptable level of losses. Expenditures for vector control include acaricides, construction of dipping or spraying facilities and their maintenance, and variable costs such as those for water and labour. Economics of vector control depend on the herd size and the method of application of the acaricide. Morbidity, mortality and tick damage losses are effectively reduced by correct and intensive vector control programmes. Expenditures for vector control are estimated at US$ 8. 43, 13.62 and 21.09 per animal per year for plunge dipping, hand spraying and pour-on, respectively. Immunization costs comprise production of parasite stabilates, storage and application, delivery and treatment. At US$ 9.5 per animal, immunization limits losses caused by Theileria parva, but ticks still may reduce the productivity of the animals. Expenditures for treatment after natural infection involve drugs, transport, veterinary fees and farm labour costs. Treatment has a moderate success rate, hence both morbidity and mortality remain important factors. Equally, it does not affect the vector, which may continue to reduce overall productivity of cattle. Expenditures for treatment range between US$ 9.04 and US$ 27.31 per animal. To compare different TECs in relation to different control strategies, assumptions have to be made on disease occurrence, case fatality, value and productivity of the cattle, reductions in productivity due to morbidity and number of animals under a specific control regime. Calculations based on data from Southern Province, Zambia show that large-scale immunization reduces the TEC by 90% compared to no intervention. Treatment, which is the second-best option, reduces the TEC by 60%. Appendix 1 Summary of factors influencing total economic cost

The efficacy and economic benefits of Paracox, a live attenuated anticoccidial vaccine, in commercial trials with standard broiler chickens in the United Kingdom.

The first large-scale broiler trials under modern commercial conditions of Paracox, a live attenuated anticoccidial vaccine administered in the drinking-water, are reported from the United Kingdom. The vaccine, comprising all seven of the species of Eimeria that parasitise the domesticated fowl, was compared with anticoccidial drug shuttles (halofuginone then salinomycin, or nicarbazin then monensin) in nine trials comprising over 936000 chickens, all of which also received the digestive enhancer virginiamycin. No clinical diseases were diagnosed in vaccinated birds in any of the trials. Necrotic enteritis occurred in the medicated controls (anticoccidial drug shuttles) of 2/9 trials and coccidiosis occurred concurrently with one of these outbreaks. Using additional criteria that particularly reflected economic benefits, the vaccine performed overall at least as well as the drug shuttles. The crucial results for vaccinated and medicated birds were: feeding costs (pence per kg liveweight of birds that were processed), 33.9 pence (vaccinated) and 33.7 pence (medicated) (P=0.549); feed conversion ratios, 2.01 (vaccinated) and 1.96 (medicated) (P=0.025); coefficient of variation in mean bird weight before processing, 9.3% (vaccinated) and 9.0% (medicated) (P=0.300); birds found dead, 3.0% (vaccinated) and 3.8% (medicated) (P<0.001); culled birds 4.0% (vaccinated) and 3.8% (medicated) (P=0.483); birds rejected during processing, 1.1% (vaccinated) and 1.2% (medicated) (P=0.271). In addition, the mean total water consumptions per chick were 7.82 L (vaccinated) and 7.76 L (medicated) (P=0.611), whilst the mean percentages of dry matter in the litter were 76.2% (vaccinated) and 75.2% (medicated) (P=0.195). Accumulation of oocysts in the litter of chicks vaccinated at 5 days of age peaked at 21 and 35 days, compared with medicated controls which showed a single higher peak at 35 days. Hence, the use of Paracox vaccine may control clinical coccidiosis in broilers and also achieve performances at least equal to anticoccidial drugs, particularly where drug resistance might result in failure to control disease.