Clinical acceptability and immunogenicity of CVD 908 Salmonella typhi vaccine strain

doi:10.1016/0264-410X(92)90392-W

Vaccine

Volume 10, Issue 7, 1992, Pages 443-446

https://doi.org/10.1016/0264-410X(92)90392-W Get rights and content

Abstract

An attenuated Salmonella typhi strain has been sought as an improved oral typhoid vaccine and as a carrier of protective antigens of other pathogens to make hybrid vaccines. Ideally, such a strain would be safe and induce protective immune responses after a single oral dose. CVD 908 is a mutant of S. typhi wild-type strain Ty2 with recombinant deletions in two genes, aroC and aroD. In phase 1 testing to date, this strain has not produced febrile responses or other significant adverse reactions in adult volunteers given doses of 5 × 10⁴ to 5 × 10⁷ organisms with sodium bicarbonate. In addition, after just a single oral dose of 5 × 10⁷ colony-forming units, this strain induced IgG seroconversion to S. typhi lipopolysaccharide in 83% of vaccinees and stimulated specific IgA-secreting gut-derived lymphocytes in 100% of vaccines. CVD 908 is a new oral typhoid vaccine that should be further investigated as a carrier for expressing foreign antigens in recombinant vaccine constructs.

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A critical consideration during nonclinical development of investigational vaccines for infectious diseases is the selection of an appropriate animal model. There is no universal animal model available for the evaluation of infectious diseases or the development of vaccines. Instead, the most appropriate animal model needs to be identified in order to meaningfully study pathophysiology and immunology of infectious disease and develop an effective vaccine. Successful interpretation of animal studies depends on understanding the similarities and differences in the immunogenic and pathophysiologic responses of the animal model to the infectious agent and vaccine, compared to humans. Choosing the most appropriate animal model is critical to guide the clinical trial design for the development of a vaccine. This chapter serves as a brief but thorough reference on established animal models for major infectious diseases and their applicability for vaccine research. At the end of this chapter, table six lists the animal models and the references for each infectious disease.
Typhoid Fever Vaccines
2017, Plotkin's Vaccines
Safety and immunogenicity of an attenuated Salmonella enterica serovar Paratyphi A vaccine candidate
2015, International Journal of Medical Microbiology
Citation Excerpt :
These vaccines were shown to be strong immunogenic. However, they caused silent vaccinemia, fever, and other adverse reactions in volunteers (Dilts et al., 2000; Tacket et al., 1992), suggesting that single mutation in the aromatic biosynthetic pathway does not satisfy the safety requirement for Salmonella live vaccine. In the present study, a further yncD mutation was introduced into S. Paratyphi A in addition to aroC mutation.
Enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased in recent years and became a global health issue. Currently licensed typhoid vaccines do not confer adequate cross-immunoprotection against S. Paratyphi A infection. Therefore, vaccines specifically against enteric fever caused by S. Paratyphi A are urgently needed. In the present study, an attenuated vaccine strain was constructed from S. Paratyphi A CMCC50093 by the deletions of aroC and yncD. The obtained strain SPADD01 showed reduced survival within THP-1 cells and less bacterial burden in spleens and livers of infected mice compared with the wild-type strain. The 50% lethal doses of SPADD01 and the wild-type strain were assessed using a murine infection model. The virulence of SPADD01 is approximately 40,000-fold less than that of the wild-type strain. In addition, SPADD01 showed an excellent immunogenicity in mouse model. Single intranasal inoculation elicited striking humoral and mucosal immune responses in mice and yielded effective protection against lethal challenge of the wild-type strain. A high level of cross-reactive humoral immune response against LPS of Salmonella enterica serovar Typhi was also detected in immunized mice. However, SPADD01 vaccination only conferred a low level of cross-protection against S. Typhi. Our data suggest that SPADD01 is a promising vaccine candidate against S. Paratyphi A infection and deserves further evaluation in clinical trial. To date, no study has demonstrated a good cross-protection between serovars of S. Typhi and S. Paratyphi A, suggesting that the dominant protective antigens of both serovars are likely different and need to be defined in future study.
Live attenuated vaccines for invasive Salmonella infections
2015, Vaccine
Citation Excerpt :
The aroC and aroD genes were deleted from Salmonella Typhi Ty2 to produce CVD 908 [72]. This vaccine was well-tolerated at doses of 5 × 104 CFU and 5 × 105 CFU and also immunogenic [19,73]. However, upon subsequent testing CVD 908 produced a clinically silent bacteremia at higher doses (5 × 107 CFU and 5 × 108 CFU) [74].
Salmonella enterica serovar Typhi produces significant morbidity and mortality worldwide despite the fact that there are licensed Salmonella Typhi vaccines available. This is primarily due to the fact that these vaccines are not used in the countries that most need them. There is growing recognition that an effective invasive Salmonella vaccine formulation must also prevent infection due to other Salmonella serovars. We anticipate that a multivalent vaccine that targets the following serovars will be needed to control invasive Salmonella infections worldwide: Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B (currently uncommon but may become dominant again), Salmonella Typhimurium, Salmonella Enteritidis and Salmonella Choleraesuis (as well as other Group C Salmonella). Live attenuated vaccines are an attractive vaccine formulation for use in developing as well as developed countries. Here, we describe the methods of attenuation that have been used to date to create live attenuated Salmonella vaccines and provide an update on the progress that has been made on these vaccines.
Irreversible covalent modification of type i dehydroquinase with a stable Schiff base
2015, Organic and Biomolecular Chemistry
The irreversible inhibition of type I dehydroquinase (DHQ1), the third enzyme of the shikimic acid pathway, is investigated by structural, biochemical and computational studies. Two epoxides, which are mimetics of the natural substrate, were designed as irreversible inhibitors of the DHQ1 enzyme and to study the binding requirements of the linkage to the enzyme. The epoxide with the S configuration caused the covalent modification of the protein whereas no reaction was obtained with its epimer. The first crystal structure of DHQ1 from Salmonella typhi covalently modified by the S epoxide, which is reported at 1.4 Å, revealed that the modified ligand is surprisingly covalently attached to the essential Lys170 by the formation of a stable Schiff base. The experimental and molecular dynamics simulation studies reported here highlight the huge importance of the conformation of the C3 carbon of the ligand for covalent linkage to this type of aldolase I enzyme, revealed the key role played by the essential His143 as a Lewis acid in this process and show the need for a neatly closed active site for catalysis.
The challenge of enteric fever
2014, Journal of Infection
Citation Excerpt :
Strain CVD 908 contains a double attenuation in two genes, aroC and aroD, that rendered it nutritionally auxotrophic for aromatic compounds that are in limited concentrations in human tissue.131 However, although immunogenic,131 silent vaccinaemias occurred in half of the volunteers who received the lower test dose of 5 × 107 cfu and all of the volunteers who ingested 5 × 108 cfu of the vaccine strain.123 Although it does not necessarily prevent licensure, the consequent requirement for enhanced pre-licensure safety data was felt to be prohibitive and efforts moved towards further attenuation to prevent vaccinaemia.
Enteric fever, a non-specific, systemic infection caused by S. Typhi or Paratyphi A, B or C, is common in resource-limited regions of the world, where poor sanitation infrastructure facilitates faeco-oral transmission. Prompt treatment with appropriate antibiotics minimises illness severity, but presentation to health care facilities is often delayed because of the non-specific nature of the symptoms and the lack of reliable diagnostic tests. Disease prevention requires significant investment in provision of clean water and sanitation in the long term; vaccination offers a more realistic strategy for medium term control. However, implementation of existing vaccines and development of more efficacious vaccines has been hindered by the lack of an established correlate of protection and under appreciation of the true disease burden. Human microbial infection studies could provide a vehicle for the rapid evaluation of novel vaccines and investigation of the immunobiology of enteric infection.

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Vaccine

Abstract

References (19)

Clinical and field trials with attenuated Salmonella typhi as live oral vaccines and as ‘carrier’ vaccines

Res. Microbiol.

Construction of genetically defined double aro mutants of Salmonella typhi

Vaccine

Identification of an intestinal immune response using peripheral blood lymphocytes

Lancet

Oral vaccination of calves against experimental salmonellosis using a double aro mutant of Salmonella typhimurium

Vaccine

Rubella viremia and antibody responses after rubella vaccination and reimmunization

Lancet

Live oral Salmonella vaccines: potential use of attenuated strains as carriers of heterologous antigens to the immune system

Parasite Immunol.

Construction of a potential live oral bivalent vaccine for typhoid fever and cholera-Escherichia coli-related diseases

Infect. Immun.

Prevention of shigellosis by a Salmonella typhi-Shigella sonnei bivalent vaccine

Infect. Immun.

Safety, immunogenicity, and efficacy against cholera challenge in man of a typhoid-cholera hybrid vaccine derived from Salmonella typhi Ty21a

Infect. Immun.

Cited by (122)

Animal Models for Infectious Disease Vaccine Development

Typhoid Fever Vaccines

Safety and immunogenicity of an attenuated Salmonella enterica serovar Paratyphi A vaccine candidate

Live attenuated vaccines for invasive Salmonella infections

Irreversible covalent modification of type i dehydroquinase with a stable Schiff base

The challenge of enteric fever