Immunity and Protection Provided by Live Modified Vaccines Against Paratyphoid Salmonella in Poultry-An Applied Perspective.

Several serotypes of non-host-specific or paratyphoid Salmonella have been linked with contamination of poultry meat, and eggs, resulting in foodborne outbreaks in humans. Vaccination of poultry against paratyphoid Salmonella is a frequent strategy used to reduce the levels of infection and transmission, which ultimately can lead to lower rates of human infections. Live vaccines have been developed and used in poultry immediately after hatching as a result of their ability to colonize the gut, stimulate a mucosal immune response, induce a competitive inhibitory effect against homologous wild strains, and reduce colonization and excretion of Salmonella. Furthermore, vaccines can competitively exclude some heterologous strains of Salmonella from colonizing the gastrointestinal tract when young poultry are immunologically immature. In addition, various studies have suggested that booster vaccination with live vaccines a few weeks after initial vaccination is essential to increase the level of protection and achieve better cross-protective immunity. Vaccination of breeders, broilers, layers, and turkeys with modified live Salmonella vaccines is a common intervention that has become an important component in poultry companies' multistep prevention programs to meet increasingly demanding customer and regulatory food safety requirements. Both live and inactivated vaccines play a critical role in a comprehensive control program for chicken and turkey breeders and commercial layers. This review examines the response and protection conferred by live modified vaccines against non-host-specific Salmonella that can be considered for the design and implementation of vaccination strategies in poultry.

Artículo regular­Inmunidad y protección que brindan las vacunas vivas modificadas contra salmonelas paratíficas en la avicultura­Una perspectiva aplicada. Varios serotipos de Salmonella paratífica no específica de huésped se han relacionado con la contaminación de la carne de pollo y huevos lo que ha provocado brotes de origen alimentario en los seres humanos. La vacunación de aves comerciales contra Salmonella paratífica es una estrategia que se utiliza con frecuencia para reducir los niveles de infección y transmisión, que en última instancia puede conducir a tasas más bajas de infecciones en humanos. Se han desarrollado y utilizado vacunas vivas en aves comerciales inmediatamente después de la eclosión como resultado de su capacidad para colonizar el intestino, estimular una respuesta inmunitaria de la mucosa, inducir un efecto inhibidor competitivo contra cepas silvestres homólogas y reducir la colonización y excreción de Salmonella. Además, las vacunas pueden excluir competitivamente algunas cepas heterólogas de Salmonella de colonizar el tracto gastrointestinal cuando las aves jóvenes son inmunológicamente inmaduras. Además, varios estudios han sugerido que la vacunación de refuerzo con vacunas vivas unas semanas después de la vacunación inicial es esencial para aumentar el nivel de protección y lograr una mejor inmunidad de protección cruzada. La vacunación de reproductoras, pollos de engorde, aves de postura y pavos con vacunas vivas modificadas contra Salmonella es una intervención común que se ha convertido en un componente importante en los programas de prevención de múltiples pasos de las empresas avícolas para cumplir con los requisitos de los clientes y regulatorios de seguridad alimentaria. Tanto las vacunas vivas como las inactivadas desempeñan un papel fundamental en un programa de control integral para productores de pollos, pavos y aves ponedoras comerciales. Esta revisión examina la respuesta y la protección conferidas por las vacunas vivas modificadas contra Salmonella no específica del huésped que pueden ser consideradas para el diseño e implementación de estrategias de vacunación en la avicultura.

Toward Control? The Prospects and Challenges of Typhoid Conjugate Vaccine Introduction.

With a newly World Health Organization (WHO)-prequalified typhoid conjugate vaccine (TCV), Gavi funding for eligible countries, and a WHO policy recommendation for TCV use, now is the time for countries to introduce TCVs as part of an integrated typhoid control program, particularly in light of the increasing burden of antimicrobial resistance. Continued vaccine development efforts will lead to secure supply of low-cost vaccines, and ongoing vaccine studies will provide critical vaccine performance data and inform optimal deployment strategies, in both routine use and in outbreak settings. TCV programs should include thoughtful communication planning and community engagement to counter vaccine hesitancy.

Evaluation of two WHO First International Standards for Vi polysaccharide from Citrobacter freundii and Salmonella enterica subspecies enterica serovar Typhi.

Numerous Vi capsular polysaccharide (Vi PS) conjugate vaccines to protect young children and infants from Typhoid are either licensed or under development. These vaccines are evaluated by laboratory methods to ensure their potency and that quality requirement are met. International Standard (IS) preparations of Vi PS are needed to calibrate and harmonise these assays. Twenty laboratories from 12 countries participated in a collaborative study to evaluate two candidate ISs: Citrobacter freundii Vi PS (NIBSC code 12/244) and Salmonella enterica serovar Typhi Vi PS (16/126). On the basis of returned results and stability profiles, these standards were established by the WHO Expert Committee on Biological Standardization in Oct 2017 as the First WHO IS for C. freundii Vi PS with a content of 1.94 ±â€¯0.12 mg Vi PS per ampoule (expanded uncertainty with coverage factor of k = 2.11 corresponding to a 95% level of confidence) and the First WHO IS for S. Typhi Vi PS with a content of 2.03 ±â€¯0.10 mg Vi PS per ampoule (expanded uncertainty with coverage factor of k = 2.11), as determined by quantitative NMR. The study also showed the ISs are suitable for physicochemical and immuno assays used for the quantitation of the Vi PS component in Vi PS and conjugate vaccines.

Vaccines for typhoid fever and other salmonelloses.

PURPOSE OF REVIEW: This review summarizes the recent advances in vaccination against Salmonella enterica serovar Typhi and highlights the data supporting the development of next generation vaccines to address paratyphoid fever and invasive nontyphoidal Salmonella (iNTS) disease. RECENT FINDINGS: There has been increasing awareness of the disease burden caused by S. Typhi particularly in Africa and greater recognition of S. Paratyphi A's contribution to enteric fever episodes throughout Asia. Groups have been working to improve the existing typhoid vaccines and provide comprehensive data on the feasibility of their implementation in endemic settings. These data have resulted in modifications to the recommendations for typhoid vaccination in traveller markets and endemic settings, and has also led to the development of S. Paratyphi A vaccine components that can be combined with existing typhoid vaccines to generate bivalent formulations against enteric fever. The epidemiology of iNTS serovars as cause of appreciable morbidity and mortality in Africa, and the need for vaccines, has also become more widely appreciated. SUMMARY: Current typhoid vaccines, although moderately effective for short periods of time, cannot be used in all age groups and only target one of the clinically relevant Salmonella serovars. Greater effort must be placed on the development and implementation of improved vaccines for the disease burden resulting from Typhi, Paratyphi A or iNTS infections.

Typhoid fever in Bangladesh: implications for vaccination policy.

OBJECTIVE: To describe the age-specific distribution of typhoid fever including the degree of Salmonella typhi bacteremia among patients evaluated at a large private diagnostic center in Bangladesh, a highly endemic area. METHODS: We conducted a prospective-, passive- and laboratory-based study to identify patients with S. typhi bacteremia. Subjects (n = 4,650) from whom blood cultures were obtained during 16-month period were enrolled from private clinics and hospitals throughout Dhaka. Isolation and quantification of S. typhi from blood cultures were performed by the lysis direct plating/ centrifugation method. RESULTS: Bacterial pathogens were recovered from blood of 538 of 4,650 patients (11.6%) evaluated. S. typhi was the single most common pathogen recovered, comprising nearly three-fourths of isolates (72.7%; 391 of 538). Isolation rate of S. typhi was highest in monsoon and summer seasons and lowest in winter months. The majority (54.5%; 213 of 391) of S. typhi isolates were from children who were younger than 5 years, and 27% (105 of 391) were from children in the first 2 years of life. The isolation rate was highest (17.4%, 68 of 486) in the second year of life. The number of bacteria in blood on the basis of colony-forming units per ml of blood by age group was inversely related to age. CONCLUSIONS: Detection of S. typhi bacteremia in young children in Dhaka, Bangladesh, was considerably higher than previously appreciated, with a peak detection rate in children < or =2 years of age, indicating the need to reassess the age-specific burden of typhoid fever in the community on a regional basis. Contrary to current recommendations this study suggests that development of new vaccines should target infants and young children.

Standardization may suffice for licensure of conjugate vaccines.

Standardization schemes devised by Control Agencies have followed clinical trials of experimental vaccines. The wealth of information about the pathogenesis of and immunity to bacteria, whose surface polysaccharides are protective antigens, now permits standardization to predict the efficacy of polysaccharide-based vaccines. There has been tacit acceptance of this notion with the licensure of groups Y and W135 meningococcal vaccines and of many of the pneumococcal types whose frequency in patients was too low for statistical significance to be assigned for their clinical efficacy. In fact, this was also the case for licensure of polio virus type 2 vaccine. We can reliably measure the level of anti-polysaccharide antibodies for meningococci, pneumococci, GBS and the Vi of S. typhi. Haemophilus type b conjugates have been reliably standardized by physico-chemical assays. New conjugates, therefore, may be licensed by data provided by standardization without awaiting the results of costly and time-consuming efficacy trials. Adoption of this scientifically-based approach to licensure will hasten the implementation of new and more effective vaccines.

Safety and immunogenicity of a live oral bivalent typhoid fever (Salmonella typhi Ty21a)-cholera (Vibrio cholerae CVD 103-HgR) vaccine in healthy adults.

The safety and immunogenicity of the live oral attenuated vaccine strains vibrio cholerae CVD 103-HgR and Salmonella typhi Ty21a were evaluated alone or in a combined bivalent formulation in four groups composed of 185 healthy European adults. All presentations were well tolerated. The serum anti-S. typhi lipopolysaccharide immunoglobulin G and immunoglobulin A antibody responses were comparable for all groups (66 to 72% seroconversion). The serum vibriocidal antibody seroconversion rate ranged from 78 to 92.5% (P > 0.05) among the groups. However, the peak and geometric mean vibriocidal antibody titers were significantly higher (P < 0.005) in the groups which received the bivalent formulation along with two doses of Ty21a than in the group which received CVD 103-HgR followed by two doses of killed Escherichia coli K-12 placebo. The ingestion of a placebo shortly after CVD 103-HgR may have suppressed the magnitude of the immune response. These findings demonstrate the feasibility of producing multivalent live oral attenuated vaccines.

Safety and immunogenicity of Salmonella typhi Ty21a vaccine in young Thai children.

Salmonella typhi Ty21a vaccine in a liquid formulation was evaluated in 634 Thai children 2 to 6 years of age. The seroconversion rate was 69% for those who received vaccine versus 14% for those who received placebo (P < 0.005). The immune responses among vaccine recipients ranged from 60% in 3-year-olds to 81% for 6-year-olds.

Comparison of the safety and immunogenicity of delta aroC delta aroD and delta cya delta crp Salmonella typhi strains in adult volunteers.

Three attenuated Salmonella typhi strains have been constructed by introducing deletions in aroC and aroD or deletions in cya and crp into one of two wild-type parent strains, Ty2 or ISP1820. These mutant strains were designated CVD 906 (ISP1820 delta aroC delta aroD), CVD 908 (Ty2 delta aroC delta aroD), and chi 3927 (Ty2 delta cya delta crp). Two studies were conducted with 36 healthy adult inpatient volunteers to determine in a double-blind fashion the safety and immunogenicity of approximately 5 x 10(4) and 5 x 10(5) CFU of each of these three vaccine candidates given as a single dose. No statistically significant difference in the incidence of reactions among vaccinees was observed. Fever (oral temperature greater than or equal to 38.2 degrees C) occurred in 2 of 12 volunteers who received CVD 906, in 0 of 12 who received CVD 908, and in 1 of 12 who received chi 3927. Vaccine bacteremia without symptoms occurred in 1 of 12 vaccinees who received CVD 906, in 0 of 12 who received CVD 908, and in 2 of 12 who received chi 3927. Overall, 19 (53%) of 36 vaccinees developed immunoglobulin G antibody to S. typhi lipopolysaccharide after vaccination, with no statistically significant differences in the rate of seroconversion among volunteers in the three groups. We conclude that defined mutations in the aromatic biosynthetic pathway and in the cyclic AMP global regulatory system attenuate S. typhi. Mutant strains CVD 906, CVD 908, and chi 3927 are highly (and approximately equally) immunogenic but possibly differ in their propensity to induce fever. Further studies are needed to document the apparent relative safety of CVD 908 as a typhoid vaccine and as a vaccine carrier of foreign antigens.

Progress in vaccines against typhoid fever.

The widely available heat-phenol-inactivated whole cell typhoid vaccine, which provides approximately 65% protection, has limited usefulness because of the adverse reactions it evokes. In contrast, several new typhoid vaccines promise protection without reactogenicity. Attenuated oral vaccine Ty21a has been evaluated in three field trials of efficacy in Santiago, Chile, involving 530,000 schoolchildren. Three doses of Ty21a in an enteric-coated formulation given within one week provided 69% efficacy for at least four years. Fewer doses conferred less protection, while adding a fourth dose significantly enhanced protection; increasing the interval between doses did not improve protection. Large-scale vaccination with Ty21a appeared to cause a herd-immunity effect. Ty21a has reached the stage of being a practical tool for public health. With respect to other vaccines, the safety and immunogenicity of an auxotrophic (Aro-,Pur-) Salmonella typhi mutant (strain 541Ty) has recently been evaluated. Lastly, parenteral purified Vi polysaccharide of S. typhi was safe and immunogenic and provided 64%-72% protection (for at least 17-21 months) in controlled field trials in Nepal and South Africa.

Safety and antigenicity of typhoid-Shigella sonnei vaccine (strain 5076-1C).

The form-1 antigen of Shigella sonnei was transferred to the avirulent Salmonella typhi strain 21a and the resulting 5076-1C transconjugate strain was tested for safety and immunogenicity as a candidate oral vaccine. The transconjugant strain was shown to be well tolerated and safe in 19 human volunteers who were fed from 1 X 10(7) to 1 X 10(10) organisms. Only two of 10 volunteers tested had developed a rise in antibody titer to the lipopolysaccharide of the hybrid 5076-1C strain.

Characteristics of the attenuated oral vaccine strain "S. typhi" Ty 21a.

The lack of a reliable in vitro test or animal model that can predict the potency of typhoid vaccines in man makes it extremely difficult to develop guidelines for the quality control of these vaccines. Attenuated S. typhi strain Ty 21a that has been shown to be safe and efficacious as live oral vaccine in clinical studies and in a controlled field trial, has been extensively characterized by genetical, biochemical and biological data. Production of live oral typhoid vaccine Ty 21a is based on a parent and working seed lot system. Characteristics of the seed lot cultures have to correspond with the original strain. Characteristics of strain Ty 21a relevant to its avirulence and potency are discussed.