Non-specific effects of inactivated Mycobacterium bovis oral and parenteral treatment in a rabbit scabies model.

Tuberculosis BCG vaccination induced non-specific protective effects in humans led to postulate the concept of trained immunity (TRAIM) as an innate type of immune mechanism that triggered by a pathogen, protects against others. Killed vaccines have been considered not to be effective. However, field efficacy of a commercial vaccine against paratuberculosis, as well as of a recently developed M. bovis heat-inactivated vaccine (HIMB) prompted to test whether it could also induce TRAIM. To this, we used a sarcoptic mange rabbit model. Twenty-four weaned rabbits were treated orally or subcutaneously with a suspension of either HIMB (107 UFC) or placebo. Eighty-four days later the animals were challenged with approximately 5000 S. scabiei mites on the left hind limb. Skin lesion extension was measured every 2 weeks until 92 days post-infection (dpi). Two animals were killed at 77 dpi because of extensive skin damage. The rest were euthanized and necropsied and the lesion area and the mite burden per squared cm were estimated. Specific humoral immune responses to S. scabiei and to M. bovis were investigated with the corresponding specific ELISA tests. Subcutaneously and orally HIMB vaccinated animals compared with placebo showed reduced lesion scores (up to 74% and 62%, respectively) and mite counts (-170% and 39%, respectively). This, together with a significant positive correlation (r = 0.6276, p = 0.0031) between tuberculosis-specific antibodies and mite count at 92 dpi supported the hypothesis of non-specific effects of killed mycobacterial vaccination. Further research is needed to better understand this mechanism to maximize cross protection.

First Investigation of the Optimal Timing of Vaccination of Nile Tilapia (Oreochromis niloticus) Larvae against Streptococcus agalactiae.

To investigate early immune responses and explore the optimal vaccination periods, Nile tilapia at 1, 7, 14, 21, 28, 35, and 42 days after yolk sac collapse (DAYC) were immersed in formalin-killed Streptococcus agalactiae vaccine (FKV-SA). A specific IgM was first detected via ELISA in the 21 DAYC larvae (0.108 g) at 336 h after vaccination (hav), whereas in the 28-42 DAYC larvae (0.330-0.580 g), the specific IgM could be initially detected at 24 hav. qRT-PCR analysis of the TCRß, CD4, MHCIIα, IgHM, IgHT, and IgHD genes in 21-42 DAYC larvae immunized with the FKV-SA immersion route for 24, 168, and 336 hav revealed that the levels of most immune-related genes were significantly higher in the vaccinated larvae at all DAYCs than in the control larvae (p < 0.05) at 336 hav. Immunohistochemistry demonstrated stronger IgM signals in the gills, head kidney, and intestine tissues at 21, 28, and 35 DAYC in all vaccinated larvae compared with the control. Interestingly, at all DAYCs, FKV-SA larvae exhibited significantly higher survival rates and an increased relative percent survival (RPS) than the control after challenge with viable S. agalactiae, particularly in larvae that were immunized with FKV-SA at 168 and 336 hav (p < 0.05).

Comparative evaluation of cell-mediated immune response in calves immunized with live-attenuated and killed Theileria annulata vaccines.

Tropical theileriosis is a tick-borne disease caused by the protozoan Theileria annulata and transmitted by numerous species of Ixodid ticks of the genus Hyalomma. The main clinical signs are fever, lymphadenopathy, and anemia responsible for heavy economic losses, including mortality, morbidity, vaccination failure, and treatment cost. Development of poor cell-mediated immunity (CMI) has been observed in the case of many bovine pathogens (bacteria, viruses, and parasites). Quantification of CMI is a prerequisite for evaluating vaccine efficacy against theileriosis caused by T. annulata. The current study evaluated the CMI in calves administered with two types of T. annulata vaccine (live attenuated and killed). We prepared a live attenuated T. annulata vaccine by attenuation in a rabbit model and also prepared killed vaccine from non-attenuated T. annulata. For the evaluation of immune response in experimental groups including control, 20 calves were divided into four different groups (A, B, C, and D). They were either inoculated subcutaneously with live rabbit-propagated-Theileria-infected RBCs (5 × 106) (group A) or with killed T. annulata vaccine (2 × 109 schizonts) with Freund's adjuvant (group B), along with an infected group (group C) and a healthy control group (group D). The protection of vaccinated calves was estimated with challenge infection. Our results showed that with a single shot of live-attenuated and killed vaccine with a booster dose elicited cell-mediated immune responses in immunized calves. We observed a significant elevation in CD4 + and CD8 + T cells in immunized calves. A significant difference in the CD8 + T cell response between the post-challenge stage of killed and live vaccine (p < 0.0001) was observed, whereas no other difference was found at both pre- and post-immunization stages. A similar finding was recorded for the CD4 + T cells at a post-challenge stage, where a significant difference was seen between killed and live vaccine (p < 0.0001). Another significant difference was observed between the CD8 + T cells and CD4 + T cells at the post-challenge stage in the live vaccine group, where there was a significantly higher induction of CD4 + T cell response (p < 0.0001).

Immune Activation Following Vaccination of Streptococcus iniae Bacterin in Asian Seabass (Lates calcarifer, Bloch 1790).

Juvenile Asian seabass (Lates calcarifer) (body weight 10 ± 0.7 g) were intraperitoneally injected with 1012 CFU fish-1 of formalin-killed Streptococcus iniae. The protective efficacy of the vaccine on survival and infection rate was assessed upon challenge at 4, 8, 12, 20, and 28 weeks post-vaccination. The results revealed that the challenged vaccinated fish showed no mortality at all time points, and the control fish presented 10-43.33% mortality. The infection rate at 2 weeks post-challenge was 0-13.33% in the vaccinated fish and 30-82.35% in the control group. At 8 weeks post-vaccination, the vaccinated fish showed comparable ELISA antibody levels with the control; however, the antibody levels of the vaccinated fish increased significantly after the challenge (p < 0.05), suggesting the presence of an adaptive response. Innate immune genes, including MHC I, MHC II, IL-1ß, IL-4/13B, and IL-10, were significantly upregulated at 12 h post-challenge in the vaccinated fish but not in the control. In summary, vaccination with S. iniae bacterin provided substantial protection by stimulating the innate and specific immune responses of Asian seabass against S. iniae infection.

Immune responses to Vibrio vulnificus formalin-killed vaccine and ghost vaccine in Scophthalmus maximus.

In this research, Vibrio vulnificus formalin-killed (FKCs) vaccine and ghost (VVGs) vaccine were successfully developed, and shown to prevent vibriosis of Scophthalmus maximus resulting from V. vulnificus. The antibody titre of FKCs and VVGs vaccine was 1: 28 and 1: 211 . The RPS of FKCs and VVGs vaccine was 60% and 80%. In order to improve the understanding of vaccine protection mechanism, transcriptome data was used to analyse the immune response of S. maximus infected with V. vulnificus after vaccination with FKCs and VVGs vaccine. In the SmCon and SmIV groups, a series of innate immune-related genes were upregulated (such as, TLR5, Tp12, AP-1 and IL-1ß) or downregulated (such as, CASP6 and CASP8), which suggested that the immune protection mechanism induced by inactivated vaccine was similar to that of autoimmune response. In the SmIV and SmGho group, a number of innate and adaptive immune-related genes (such as, STAT1, IFN-γ and MHC Ia) were activated, in which the expression of these genes was higher in SmGho, and VVGs vaccine induced stronger innate and acquired immune responses. In conclusion, the results lay a foundation for further study on the molecular mechanisms of immune protection induced by VVGs vaccine and FKCs vaccine.

Effect of Killed PRRSV Vaccine on Gut Microbiota Diversity in Pigs.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens affecting the global swine industry. Vaccination is still a main strategy for PRRSV control; however, host factors associated with vaccine efficacy remain poorly understood. Growing evidence suggests that mucosa-associated microbiomes may play a role in the responses to vaccination. In this study, we investigated the effects of a killed virus vaccine on the gut microbiome diversity in pigs. Fecal microbial communities were longitudinally assessed in three groups of pigs (vaccinated/challenged with PRRSV, unvaccinated/challenged with PRRSV, and unvaccinated/unchallenged) before and after vaccination and after viral challenge. We observed significant interaction effects between viral challenge and vaccination on both taxonomic richness and community diversity of the gut microbiota. While some specific taxonomic alterations appear to be enhanced in vaccinated/challenged pigs, others appeared to be more consistent with the levels in control animals (unvaccinated/unchallenged), indicating that vaccination incompletely protects against viral impacts on the microbiome. The abundances of several microbial taxa were further determined to be correlated with the level of viral load and the amount of PRRSV reactive CD4+ and CD8+ T-cells. This study highlights the potential roles of gut microbiota in the response of pigs to vaccination, which may pave the road for the development of novel strategies to enhance vaccine efficacy.

Three Models of Vaccination Strategies Against Cryptococcosis in Immunocompromised Hosts Using Heat-Killed Cryptococcus neoformans Δsgl1.

Vaccines are one of the greatest medical accomplishments to date, yet no fungal vaccines are currently available in humans mainly because opportunistic mycoses generally occur during immunodeficiencies necessary for vaccine protection. In previous studies, a live, attenuated Cryptococcus neoformans Δsgl1 mutant accumulating sterylglucosides was found to be avirulent and protected mice from a subsequent lethal infection even in absence of CD4+ T cells, a condition most associated with cryptococcosis (e.g., HIV). Here, we tested three strategies of vaccination against cryptococcosis. First, in our preventative model, protection was achieved even after a 3-fold increase of the vaccination window. Second, because live C. neoformans Δsgl1-vaccinated mice challenged more than once with WT strain had a significant decrease in lung fungal burden, we tested C. neoformans Δsgl1 as an immunotherapeutic. We found that therapeutic administrations of HK C. neoformans Δsgl1 post WT challenge significantly improves the lung fungal burden. Similarly, therapeutic administration of HK C. neoformans Δsgl1 post WT challenge resulted in 100% or 70% survival depending on the time of vaccine administration, suggesting that HK Δsgl1 is a robust immunotherapeutic option. Third, we investigated a novel model of vaccination in preventing reactivation from lung granuloma using C. neoformans Δgcs1. Remarkably, we show that administration of HK Δsgl1 prevents mice from reactivating Δgcs1 upon inducing immunosuppression with corticosteroids or by depleting CD4+ T cells. Our results suggest that HK Δsgl1 represents a clinically relevant, efficacious vaccine that confers robust host protection in three models of vaccination against cryptococcosis even during CD4-deficiency.

Pre-treatment of Nile tilapia (Oreochromis niloticus) with ozone nanobubbles improve efficacy of heat-killed Streptococcus agalactiae immersion vaccine.

Nanobubble technology has shown appealing technical benefits and potential applications in aquaculture. We recently found that treatment with ozone nanobubbles (NB-O3) activated expression of several immune-related genes leading to effective response to subsequent exposure to fish pathogens. In this study, we investigated whether pre-treatment of Nile tilapia (Oreochromis niloticus) with NB-O3 can enhance specific immune responses and improve efficacy of immersion vaccination against Streptococcus agalactiae. Spleen and head kidney of fish in the vaccinated groups showed a substantial upregulation in expression levels of pro-inflammatory cytokine genes (IL-1ß, TNF-α, IL-6) and immunoglobulin classes (IgM, IgD, IgT) compared with the unvaccinated control groups. The mRNA transcript of pro-inflammatory cytokine genes was greatest (approx. 2.8-3.3 folds) on day 7 post-vaccination, whereas the relative expression of immunoglobulin genes was greatest (approx. 3.2-4.1 folds) on day 21 post-immunization. Both systemic and mucosal IgM antibodies were elicited in vaccinated groups. As the result, the cumulative survival rate of the vaccinated groups was found to be higher than that of the unvaccinated groups, with a relative percent survival (RPS) ranging from 52.9 to 70.5%. However, fish in the vaccinated groups that received pre-treatment with NB-O3, bacterial antigen uptakes, expression levels of IL-1ß, TNF-α, IL-6,IgM, IgD, and IgT, as well as the specific-IgM antibody levels and percent survival, were all slightly or significantly higher than that of the vaccinated group without pre-treatment with NB-O3. Taken together, our findings suggest that utilizing pre-treatment with NB-O3 may improve the immune response and efficacy of immersion vaccination in Nile tilapia.

Fundamentals of Fish Vaccination.

Fish health management has become a critical component of disease control and is invaluable for improved harvests and sustainable aquaculture. Vaccination is generally accepted as the most effective prophylactic measure for fish disease prevention, on environmental, social, and economic grounds. Although the historical approach for developing fish vaccines was based on the principle of Louis Pasteur's "isolate, inactivate and inject," but their weak immunogenicity and low efficacies in many cases, have shifted the focus of fish vaccine development from traditional to next-generation technologies. However, before any fish vaccine can be successfully commercialized, several hurdles need to be overcome regarding the production cost, immunogenicity, effectiveness, mode of administration, environmental safety, and associated regulatory concerns. In this context, the chapter summarises the basic aspects of fish vaccination such as type of vaccine, modalities of vaccine delivery, the immunological basis of fish immunization as well as different challenges associated with the development process and future opportunities.

Controlling the Colonization of Clostridium perfringens in Broiler Chickens by an Electron-Beam-Killed Vaccine.

Clostridium perfringens (Cp) is a Gram-positive anaerobe that is one of the causative agents of necrotic enteritis (NE) in chickens, which leads to high mortality. Owing to the ban of administering antibiotics in feed to chickens, there has been an increase in the number of NE outbreaks all over the world, and the estimated loss is approximately 6 billion U.S. dollars. The best alternative method to control NE without antibiotics could be vaccination. In this study, we exposed three different strains of Cp to electron beam (eBeam) irradiation to inactivate them and then used them as a killed vaccine to control the colonization of Cp in broiler chickens. The vaccine was delivered to 18-day old embryos in ovo and the chickens were challenged with the respective vaccine strain at two different time points (early and late) to test the protective efficacy of the vaccine. The results indicate that an effective eBeam dose of 10 kGy inactivated all three strains of Cp, did not affect the cell membrane or epitopes, induced significant levels of IgY in the vaccinated birds, and further reduced the colonization of Cp strains significantly (p < 0.0001) in late challenge (JGS4064: 4 out of 10; JGS1473: 0 out of 10; JGS4104: 3 out of 10). Further studies are necessary to enhance the efficacy of the vaccine and to understand the mechanism of vaccine protection.

Adjuvanted vaccines driven protection against visceral infection in BALB/c mice by Leishmania donovani.

Kinteoplastid protozoan parasite of genus Leishmania is the pathogen that causes leishmaniasis. Its prevalence is highest after malaria and visceral leishmaniasis is the most dreaded form of infection. No vaccine is available for the disease management and it relies wholly on a few chemotherapeutic agents which are toxic and besides drug resistance their costs are the limitations. Therefore, development of an effective vaccine is urgently required. In this study, Montanide ISA 201 and AddaVax were assessed for their adjuvant potential along with formalin-inactivated or killed vaccine for the immune induction. Immunological and parasitological studies were conducted to evaluate the efficacy of different vaccine formulations in BALB/c mice before challenge infection as well as 4, 8, and 12 weeks after challenge. The efficacy of vaccines was evidenced with reduced parasite burden, the higher DTH response, Th1 cytokines, and IgG2a isotype antibody in immunized mice. All the vaccines showed their potential against Leishmania donovani infection and vaccine formulated with Montanide ISA 201 exhibited maximum efficacy. Our results suggest the potential of these vaccine formulations in controlling Leishmania infection.

Efficacy of Whole Cell Inactivated Vibrio harveyi Vaccine against Vibriosis in a Marine Red Hybrid Tilapia (Oreochromis niloticus × O. mossambicus) Model.

Vibrio harveyi causes vibriosis in various commercial marine fish species. The infection leads to significant economic losses for aquaculture farms, and vaccination is an alternative approach for the prevention and control of fish diseases for aquaculture sustainability. This study describes the use of formalin-killed Vibrio harveyi (FKVh) strain Vh1 as a vaccine candidate to stimulate innate and adaptive immunities against vibriosis in a marine red hybrid tilapia model. Tilapia are fast growing; cheap; resistant to diseases; and tolerant to adverse environmental conditions of fresh water, brackish water, and marine water and because of these advantages, marine red hybrid tilapia is a suitable candidate as a model to study fish diseases and vaccinations against vibriosis. A total of 180 healthy red hybrid tilapias were gradually adapted to the marine environment before being divided into two groups, with 90 fish in each group and were kept in triplicate with 30 fish per tank. Group 1 was vaccinated intraperitoneally with 100 µL of FKVh on week 0, and a booster dose was similarly administered on week 2. Group 2 was similarly injected with PBS. Skin mucus, serum, and gut lavage were collected weekly for enzyme-linked immunosorbent assay (ELISA) and a lysozyme activity assay from a total of 30 fish of each group. On week 4, the remaining 60 fish of Groups 1 and 2 were challenged with 108 cfu/fish of live Vibrio harveyi. The clinical signs were monitored while the survival rate was recorded for 48 h post-challenge. Vaccination with FKVh resulted in a significantly (p < 0.05) higher rate of survival (87%) compared to the control (20%). The IgM antibody titer and lysozyme activities of Group 1 were significantly (p < 0.05) higher than the unvaccinated Groups 2 in most weeks throughout the experiment. Therefore, the intraperitoneal exposure of marine red hybrid tilapia to killed V. harveyi enhanced the resistance and antibody response of the fish against vibriosis.

Histopathological changes of reproductive organs of goats immunized with Corynebacterium pseudotuberculosis killed vaccine.

Caseous lymphadenitis (CLA) caused by Corynebacterium pseudotuberculosis is characterized by the development of abscesses, mainly in superficial and internal lymph nodes, visceral and reproductive organs in small ruminants. This study aims to examine the histopathological changes in reproductive organs of goats immunized with killed vaccine of C. pseudotuberculosis. In this study, twenty four (24) clinically healthy bucks and does were divided into four groups A, B, C and D. Animals in groups A and B were immunized with 0.5 and 1% formalin killed vaccine, respectively; followed by a booster dose. After the booster dose of immunization, groups A, B and C were challenged with C. pseudotuberculosis at 106 cfu/ml. Goats in group D were immunize and unchallenged and left as control group. All C. pseudotuberculosis infected animals were euthanized humanely 12 weeks post-challenged. Tissue samples such as testes, epididymis, spermatic cord, penis, pituitary gland, mammary gland, vulva, vagina, cervix, uterus, fallopian tube and ovaries were collected for histopathology study. Microscopic examination of all tissues (testes, seminiferous tubules, spermatic cord, penile tissues and the pituitary gland) in the male reproductive organs of the bucks that were inoculated with 2 ml of 0.5% and 1.0% of C. pseudotuberculosis killed vaccine showed normal (animals inoculated with 1.0%) to mild (animals inoculated with 0.5%) histopathological changes when compared with those from group C which showed varying degrees of histopathological changes (p < 0.01) in their various tissues. For the female does, similar histopathological changes were observed for the various tissues examined (ovaries, fallopian tubes, uterine horns, uterine tissues, cervix, vaginal, vulva, mammary glands and the pituitary glands) in which the vaccinated groups A &B showed a significantly (p < 0.001) less histopathological changes when compared with those in group C that showed varying degrees of histopathological changes in the reproductive organs investigated. This study showed the efficacy of C. pseudotuberculosis killed vaccine protecting against reproductive tissue damages cause by the active infection with the live bacteria in both bucks and does in the study area.

Immune Responses and Protective Efficacy of a Formalin-Killed Francisella Noatunensis Subsp. Orientalis Vaccine Evaluated through Intraperitoneal and Immersion Challenge Methods in Oreochromis Niloticus.

Francisella noatunensis subsp. orientalis (Fno), an intracellular bacterium, causes systemic granulomatous diseases, resulting in high mortality and huge economic losses in Taiwanese tilapia farming. In this study, we tested the efficacy of a formalin-killed Fno vaccine in cultured tilapia. Fno was isolated from diseased tilapia, inactivated with formalin, and mixed with the mineral oil base adjuvant (MontanideTM ISA 763 AVG). A total of 300 tilapia were divided into two groups. The experimental group was intraperitoneally injected with 0.1 mL of vaccine, which was substituted with phosphate-buffered saline (PBS) in the control group. A booster was administered at 2 weeks post-immunization. Tilapia were challenged at 6 weeks post primary immunization by intraperitoneal (IP) injection and immersion methods. Mortality was recorded at 21 and 60 days. The results revealed that the vaccine induced a greater antibody titer and led to 71% and 76% of relative percent survival (RPS) after the IP and immersion challenge. The transcripts of proinflammatory cytokines and immune-related genes, including interleukin-1ß (IL-1ß), tumor necrosis factor alpha (TNFα), C-X-C motif chemokine ligand 8 (CXCL8), and interleukin-17C (IL-17C), were significantly upregulated after vaccination. Additionally, vaccinated fish had lower bacterial loads in the blood and lower granuloma intensities in the kidney, spleen, liver, and gill than control fish. The results in this study demonstrate that the inactivated Fno vaccine could be an essential resource in Taiwanese tilapia farming.

Poly (d,l-lactide-co-glycolide) nanoparticle-entrapped vaccine induces a protective immune response against porcine epidemic diarrhea virus infection in piglets.

Porcine epidemic diarrhea (PED) causes 80-100% mortality in neonatal piglets, and its causative agent, the porcine epidemic diarrhea virus (PEDV), poses an important threat to the swine industry worldwide. In this study, we prepared biodegradable poly (d,l-lactide-co-glycolide) (PLGA) nanoparticle-entrapped PEDV killed vaccine antigens (KAg) (PLGA-KAg). Late-term pregnant sows were intranasally inoculated with PLGA-KAg, and the mortality resulting from challenge with highly virulent PEDV was investigated in their passively immunized suckling piglets. PEDV-specific IgG and IgA antibody titers were enhanced in pregnant sows immunized with PLGA-KAg relative to the titers in sows inoculated with KAg. Similar results were seen in the passively immunized suckling piglets of these sows. Improved lymphocyte proliferation responses and IFN-γ levels were induced in pregnant sows immunized with PLGA-KAg compared with those vaccinated with KAg or with Montanide™ ISA 201 VG emulsified killed PEDV vaccine (201-KAg). Importantly, there was less piglet mortality in the group vaccinated with PLGA-KAg than in the groups vaccinated with KAg or 201-KAg. These results demonstrate that PLGA-KAg is a promising candidate vaccine that can provide protective immunity against PEDV infection in suckling piglets.

RNA-Seq transcriptome analysis of the olive flounder (Paralichthys olivaceus) kidney response to vaccination with heat-inactivated viral hemorrhagic septicemia virus.

Viral hemorrhagic septicemia (VHS) is a highly contagious disease of cultured flounder caused by VHS virus (VHSV). To develop effective VHSV vaccines, it is essential to understand the molecular mechanisms underlying the host's protective response against VHSV. The purpose of this study is to clarify which genes are involved in the protective response of olive flounder after VHSV vaccination. We first injected olive flounder intraperitoneally with 107 TCID50 heat-inactivated VHSV vaccine and evaluated the vaccine efficacy at 20 °C. Fish vaccinated with heat-inactivated VHSV were significantly protected compared to non-vaccinated fish, with a relative percentage survival of 83%. To analyze the vaccination-induced changes in the expression profiles of genes, kidneys were collected from control and vaccinated fish at days 1, 3, and 7 after vaccination and global gene expression profiling was carried out by RNA sequencing. The analysis revealed that 15,001 genes were differentially expressed by at least 2-fold between vaccinated fish and non-vaccinated controls. Of these, 58 genes clustered into the acute phase response, Toll-like receptor, interferon-inducible/regulatory proteins, and apoptosis pathways. These data provided insights into the molecular mechanisms underlying the protective immune response of olive flounder against heat-inactivated VHSV vaccine and might aid future studies to develop a highly immunogenic vaccine against VHSV in flounder.

Application of radiation technology in vaccines development.

One of the earliest methods used in the manufacture of stable and safe vaccines is the use of chemical and physical treatments to produce inactivated forms of pathogens. Although these types of vaccines have been successful in eliciting specific humoral immune responses to pathogen-associated immunogens, there is a large demand for the development of fast, safe, and effective vaccine manufacturing strategies. Radiation sterilization has been used to develop a variety of vaccine types, because it can eradicate chemical contaminants and penetrate pathogens to destroy nucleic acids without damaging the pathogen surface antigens. Nevertheless, irradiated vaccines have not widely been used at an industrial level because of difficulties obtaining the necessary equipment. Recent successful clinical trials of irradiated vaccines against pathogens and tumors have led to a reevaluation of radiation technology as an alternative method to produce vaccines. In the present article, we review the challenges associated with creating irradiated vaccines and discuss potential strategies for developing vaccines using radiation technology.

BVDV vaccination in North America: risks versus benefits.

The control and prevention of bovine viral diarrhea virus (BVDV) infections has provided substantial challenges. Viral genetic variation, persistent infections, and viral tropism for immune cells have complicated disease control strategies. Vaccination has, however, provided an effective tool to prevent acute systemic infections and increase reproductive efficiency through fetal protection. There has been substantial controversy about the safety and efficacy of BVDV vaccines, especially when comparing killed versus modified-live viral (MLV) vaccines. Furthermore, numerous vaccination protocols have been proposed to protect the fetus and ensure maternal antibody transfer to the calf. These issues have been further complicated by reports of immune suppression during natural infections and following vaccination. While killed BVDV vaccines provide the greatest safety, their limited immunogenicity makes multiple vaccinations necessary. In contrast, MLV BVDV vaccines induce a broader range of immune responses with a longer duration of immunity, but require strategic vaccination to minimize potential risks. Vaccination strategies for breeding females and young calves, in the face of maternal antibody, are discussed. With intranasal vaccination of young calves it is possible to avoid maternal antibody interference and induce immune memory that persists for 6-8 months. Thus, with an integrated vaccination protocol for both breeding cows and calves it is possible to maximize disease protection while minimizing vaccine risks.

Developing whole mycobacteria cell vaccines for tuberculosis: Workshop proceedings, Max Planck Institute for Infection Biology, Berlin, Germany, July 9, 2014.

On July 9, 2014, Aeras and the Max Planck Institute for Infection Biology convened a workshop entitled "Whole Mycobacteria Cell Vaccines for Tuberculosis" at the Max Planck Institute for Infection Biology on the grounds of the Charité Hospital in Berlin, Germany, close to the laboratory where, in 1882, Robert Koch first identified Mycobacterium tuberculosis (Mtb) as the pathogen responsible for tuberculosis (TB). The purpose of the meeting was to discuss progress in the development of TB vaccines based on whole mycobacteria cells. Live whole cell TB vaccines discussed at this meeting were derived from Mtb itself, from Bacille Calmette-Guérin (BCG), the only licensed vaccine against TB, which was genetically modified to reduce pathogenicity and increase immunogenicity, or from commensal non-tuberculous mycobacteria. Inactivated whole cell TB and non-tuberculous mycobacterial vaccines, intended as immunotherapy or as safer immunization alternatives for HIV+ individuals, also were discussed. Workshop participants agreed that TB vaccine development is significantly hampered by imperfect animal models, unknown immune correlates of protection and the absence of a human challenge model. Although a more effective TB vaccine is needed to replace or enhance the limited effectiveness of BCG in all age groups, members of the workshop concurred that an effective vaccine would have the greatest impact on TB control when administered to adolescents and adults, and that use of whole mycobacteria cells as TB vaccine candidates merits greater support, particularly given the limited understanding of the specific Mtb antigens necessary to generate an immune response capable of preventing Mtb infection and/or disease.

Transmission Dynamics of Rift Valley Fever Virus: Effects of Live and Killed Vaccines on Epizootic Outbreaks and Enzootic Maintenance.

Rift Valley fever virus (RVFV) is an arthropod-borne viral pathogen that causes significant morbidity and mortality in small ruminants throughout Africa and the Middle East. Due to the sporadic and explosive nature of RVF outbreaks, vaccination has proved challenging to reduce RVFV infection in the ruminant population. Currently, there are two available types of vaccines, live and killed, in endemic areas. In this study, two mathematical models have been developed to explore the impact of live and killed vaccines on the transmission dynamics of RVFV. We demonstrate in general that vaccination helps reduce the severity of RVF outbreaks and that less delay in implementation and more vaccination attempts and effective vaccines can reduce the outbreak magnitude and the endemic number of RVFV. However, an introduction of a number of ruminants vaccinated by live vaccines in RVFV-free areas may cause an outbreak and RVFV may become endemic if there is sustained use of live vaccines. Other factors that are the important determinants of RVF outbreaks include: unsustained vaccination programs, recruitment of susceptible ruminants, and the seasonal abundance of mosquitoes.