Recombinant bacterial vaccines

doi:10.1016/j.coi.2012.03.013

Current Opinion in Immunology

Volume 24, Issue 3, June 2012, Pages 337-342

https://doi.org/10.1016/j.coi.2012.03.013 Get rights and content

Vaccines are currently available for many infectious diseases caused by several microbes and the prevention of disease and death by vaccination has profoundly improved public health globally. However, vaccines are not yet licensed for use against many other infectious diseases and new or improved vaccines are needed to replace suboptimal vaccines, and against newly emerging pathogens. Most of the vaccines currently licensed for human use include live attenuated and inactivated or killed microorganisms. Only a small subset is based on purified components and even fewer are recombinantly produced. Novel approaches in recombinant DNA technology, genomics and structural biology have revolutionized the way vaccine candidates are developed and will make a significant impact in the generation of safer and more effective vaccines.

Highlights

► The advantages and disadvantages of recombinant bacterial vaccines are discussed with relevant examples. ► Recombinant subunit vaccines are safer but have a demanding manufacturing process. ► Recombinant whole cell vaccines demonstrate better immunogenicity but represent a regulatory challenge due the safety concerns. ► Recombinant bacterial carriers are being developed for delivery of vaccines toward infectious as well as metabolic diseases. ► New approaches like structural vaccinology are key in vaccine design against antigens that are highly variable.

Introduction

Vaccines for infectious diseases have come a long way, starting from the Jenner's cowpox vaccines two centuries ago to the present day vaccines designed using recent technologies like reverse and structural vaccinology. The field of vaccinology, primarily founded on Pasteur's principles has yielded several effective vaccines. In fact, today, the vast majority of licensed vaccines are live attenuated or killed/inactivated microorganisms [1]. However, given that there are still several deadly diseases that lack an efficient vaccine, it is becoming pertinent to apply newer technologies to quicken the search for better and safer vaccines [2]. The advent of genetic engineering has given scientists the ability to rationally design both individual microbial components as well as whole organisms. Furthermore, the application of functional genomics and structural biology has allowed the identification of many promising new antigens. Although at present there are few licensed vaccines that are based on recombinant technology, it is quite clear that novel genetic technologies have a crucial role to fulfill in the years to come. The aim of this review is to illustrate the use of recombinant DNA technology in bacterial vaccine development using examples of existing and future vaccines.

Section snippets

Recombinant subunit vaccines

The main drivers for recombinant protein-based vaccine development are developing less reactogenic, more potent, safer, better characterized vaccines, in addition to developing vaccines that provide broader protection against multiple serotypes/serogroups of a bacterium. The first of these vaccines was the highly pure surface antigen of the hepatitis B virus expressed in yeast [3]. The second, a Bordetella pertussis subunit vaccine (acellular vaccine) containing three highly pure proteins

Recombinant bacterial strains

Whole cell vaccines are a common vaccine strategy for many diseases, especially when the immune responses involved are complex. Historically, many attenuated vaccine strains like Bacille Calmette Guerin (BCG) and Salmonella typhi Ty21a were generated by continuous passage or chemical mutagenesis [20]. With recombinant technology, pathogens can now be manipulated to generate non virulent, but immunogenic strains. Targeted attenuated mutants of various human pathogens have shown promise in animal

Vaccines based on protein structure

Structural vaccinology, a recent approach based on the use of information derived from protein structure and epitope mapping can be used in the rational design of new recombinant vaccines, particularly against antigens characterized by a complex antigenic variability. This approach has been applied to design fully synthetic proteins to induce multivalent protection. Cell surface pili, protective antigens of GBS, exist as six immunogenically different but structurally similar variants. Based on

Conclusions

Recombinant DNA technology has indeed changed the face of vaccinology by enabling rational design vaccines against complex human diseases (Figure 1). Despite excellent evidence of success of recombinant vaccines in pre-clinical and clinical studies, few recombinant vaccines are licensed for human use. This can however be attributed to the intense regulatory processes revolving around recombinant vaccine production. Improved adjuvant technologies, new approaches like systems biology and advanced

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (51)

R. Rappuoli et al.
Vaccine discovery and translation of new vaccine technology
Lancet
(2011)
F.E. Andre
Overview of a 5-year clinical experience with a yeast-derived hepatitis B vaccine
Vaccine
(1990)
R. Rappuoli
Reverse vaccinology, a genome-based approach to vaccine development
Vaccine
(2001)
M.D. Snape et al.
Immunogenicity and reactogenicity of a 13-valent-pneumococcal conjugate vaccine administered at 2, 4, and 12 months of age: a double-blind randomized active-controlled trial
Pediatr Infect Dis J
(2010)
G. Madico et al.
Factor H binding and function in sialylated pathogenic neisseriae is influenced by gonococcal, but not meningococcal, porin
J Immunol
(2007)
C. Harro et al.
A combination vaccine consisting of three live attenuated enterotoxigenic Escherichia coli strains expressing a range of colonization factors and heat-labile toxin subunit B is well tolerated and immunogenic in a placebo-controlled double-blind phase I trial in healthy adults
Clin Vaccine Immunol
(2011)
G.A. Colditz et al.
Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature
JAMA
(1994)
E.L. Hohmann et al.
Evaluation of a phoP/phoQ-deleted, aroA-deleted live oral Salmonella typhi vaccine strain in human volunteers
Vaccine
(1996)
G. Xiong et al.
Novel cancer vaccine based on genes of Salmonella pathogenicity island 2
Int J Cancer
(2010)
R. Singh et al.
Cancer immunotherapy using recombinant Listeria monocytogenes: transition from bench to clinic
Hum Vaccin
(2011)

P.B. Keiser et al.

A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression

Vaccine

(2011)

V.B. Pinto et al.

An experimental outer membrane vesicle vaccine from N. meningitidis serogroup B strains that induces serum bactericidal activity to multiple serogroups

Vaccine

(2011)

A. Nuccitelli et al.

Structure-based approach to rationally design a chimeric protein for an effective vaccine against Group B Streptococcus infections

Proc Natl Acad Sci USA

(2011)

M. Scarselli et al.

Rational design of a meningococcal antigen inducing broad protective immunity

Sci Transl Med

(2011)

M.F. Feldman et al.

Engineering N-linked protein glycosylation with diverse O antigen lipopolysaccharide structures in Escherichia coli

Proc Natl Acad Sci USA

(2005)

J. Ihssen et al.

Production of glycoprotein vaccines in Escherichia coli

Microb Cell Fact

(2010)

S.A. Plotkin et al.

The development of vaccines: how the past led to the future

Nat Rev Microbiol

(2011)

M. Pizza et al.

Mutants of pertussis toxin suitable for vaccine development

Science

(1989)

J.D. Campbell et al.

Safety, reactogenicity and immunogenicity of a recombinant protective antigen anthrax vaccine given to healthy adults

Hum Vaccin

(2007)

B.K. Brown et al.

Phase I study of safety and immunogenicity of an Escherichia coli-derived recombinant protective antigen (rPA) vaccine to prevent anthrax in adults

PLoS ONE

(2010)

M. Pizza et al.

Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing

Science

(2000)

M.M. Giuliani et al.

A universal vaccine for serogroup B meningococcus

Proc Natl Acad Sci USA

(2006)

J. Findlow et al.

Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy

Clin Infect Dis

(2010)

A. Kimura et al.

Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates

Clin Vaccine Immunol

(2011)

M.E. Santolaya et al.

Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study

Lancet

(2012)

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Novel development of cationic surfactant-based mucoadhesive nanovaccine for direct immersion vaccination against Francisella noatunensis subsp. orientalis in red tilapia (Oreochromis sp.)
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Citation Excerpt :
One of the most effective strategies to protect fish, especially small fish and fry, against infectious diseases in the fields is immersion vaccination [5]. Most of traditional fish vaccines are normally prepared in the forms of live attenuated or killed microorganisms [35,36]. This includes Fno vaccine [6–8], which is usually utilized for injection route.
Francisella noatunensis subsp. orientalis (Fno) is one of the infectious diseases that causes economic losses associated with tilapia mortality. Even though direct immersion administration of vaccines is more practicable for small fish and fry compared with oral and injection vaccination in the fields, the efficacy is still insufficient due to lower potency of antigen uptake. Herein, we accomplished the development of a mucoadhesive nanovaccine platform using cetyltrimethylammonium bromide (CTAB), a cationic surfactant, to improve the efficiency of immersion vaccination against Fno in tilapia. Cationic Fno nanovaccine (CAT-Fno-NV) was prepared though emulsification using an ultrasonic method. In our investigation, the CAT-Fno-NV increased the opportunity of Fno vaccine uptake by extending the contact time between vaccine and mucosal surface of fish gills and enhancing the protective efficacy against Fno infection. Fish were vaccinated with the CAT-Fno-NV by a direct immersion protocol. The challenge trial by Fno injection revealed that CAT-Fno-NV at the concentration 1:100 ratio (approximately 1 × 10⁶ cfu/mL) had the highest efficacy to protect fish from Fno infection at day 30 after post challenge period according to the total number of Fno detected in head kidney, spleen and liver. A significant upregulation of IgM gene was observed in gills, skin, head kidney, serum and peripheral blood lymphocytes (PBLs) and spleen tissues treated with WC and CAT-Fno-NV (1:100) vaccines, while IgT gene was highly expressed in only gills and skin tissues for treated WC and CAT-Fno-NV (1:100) groups. We anticipate that the cationic surfactant-based nanovaccine developed in this study could become an efficient alternative for direct immersion vaccination to induce humoral immune responses against Fno in vaccinated tilapia.
Bacterial Vaccines
2022, Encyclopedia of Infection and Immunity
The development of vaccines is the greatest achievement of modern medicine. These vaccines can prevent population- and healthcare associated infections with susceptible as well as multidrug-resistant (MDR) microbes, minimize antimicrobial use and resistance, and avoid infection in all age groups, specifically older adults. The bacterial vaccines are divided in different categories including toxoids, polysaccharide vaccines, conjugate vaccines, inactive vaccines, live attenuated vaccines and recombinant vaccines. In general, all of these vaccine categories have certain advantages and downsides, and their usage is dependent on understanding of the immune evasion mechanisms used by bacteria, the site of infection and T-cell mediated mucosal infection control processes. In this article, we highlight vaccine types and use, some of the main advancements made, new techniques and methods for vaccine development, as well as potential flaws and hazards.
Computational approaches for vaccine designing
2021, Bioinformatics: Methods and Applications
Traditional approaches to design a vaccine have failed in providing broad spectrum and long-term protection against various bacterial and viral infections. In the postgenomic era, identification of a specific antigenic region for activating a specific arm of an immune system has been the greatest challenge. To address this critical issue, in the last two decades vaccine designing has become a significant field of interest for researchers. Numerous web-based resources have been developed, which have proved extremely helpful in in silico vaccine designing. In this chapter, we discussed computational tools designed for the antigen selection and related immunological databases, in silico tools developed for linear and conformational B-cell epitope prediction, resources developed for T-cell epitopes or MHC class I and II binders, and tools developed for other miscellaneous properties of vaccines, such as toxicity, half-life, and delivery. In the end, we also discussed the role of next-generation sequencing technologies in vaccine development.
Enhanced efficacy of immersion vaccination in tilapia against columnaris disease by chitosan-coated “pathogen-like” mucoadhesive nanovaccines
2019, Fish and Shellfish Immunology
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As compared to inactivated vaccines, live attenuated vaccines can be highly effective [19,20]. However, their potential risk of reversion of the microorganism for a more virulent phenotype can occur [15,21]. This major concern has become a limitation for their use in aquaculture including in Thailand.
Red tilapia (Oreochromis sp.) has become one of the most important fish in aquaculture. Bacterial infection caused by Flavobacterium columnare, the causative agent of columnaris disease, has been now identified as one of the most serious infectious diseases in farmed red tilapia and cause major financial damage to the producers. Among the effective prevention and control strategies, vaccination is one of the most effective approach. As the surface of living fish is covered by mucus and directly associated with the mucosal immunity, we therefore hypothesized that better adsorption on mucosal surfaces and more efficient vaccine efficacy could be enhanced biomimetic nanoparticles mimicking the mucoadhesive characteristic of live F. columnare. In this work, we describe an effective approach to targeted antigen delivery by coating the surface of nanoparticles with mucoadhesive chitosan biopolymer to provide “pathogen-like” properties that ensure nanoparticles binding on fish mucosal membrane. The physiochemical properties of nanovaccines were analyzed, and their mucoadhesive characteristics and immune response against pathogens were also evaluated. The prepared vaccines were nano-sized and spherical as confirmed by scanning electron microscope (SEM). The analysis of hydrodynamic diameter and zeta-potential also suggested the successful modification of nanovaccines by chitosan as indicated by positively charged and the overall increased diameter of chitosan-modified nanovaccines. In vivo mucoadhesive study demonstrated the excellent affinity of the chitosan-modified nanovaccines toward fish gills as confirmed by bioluminescence imaging, fluorescent microscopy, and spectrophotometric quantitative measurement. Following vaccination with the prepared nanovaccines by immersion 30 min, the challenge test was then carried out 30 and 60 days post-vaccination and resulted in high mortalities in the control. The relative percent survival (RPS) of vaccinated fish was greater than 60% for mucoadhesive nanovaccine. Our results also suggested that whole-cell vaccines failed to protect fish from columnaris infection, which is consistent with the mucoadhesive assays showing that whole-cell bacteria were unable to bind to mucosal surfaces. In conclusion, we could use this system to deliver antigen preparation to the mucosal membrane of tilapia and obtained a significant increase in survival compared to controls, suggesting that targeting mucoadhesive nanovaccines to the mucosal surface could be exploited as an effective method for immersion vaccination.
Mucosal and systemic responses of immunogenic vaccines candidates against enteric Escherichia coli infections in ruminants: A review
2018, Microbial Pathogenesis
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In simple intestinal and airway epithelia whose intercellular spaces are sealed by tight junctions, specific epithelial M cells deliver antigen through transepithelial conveyance from the lumen to structured lymphoid tissues located in the mucosa [7,8]. These days, the enormous mainstream of approved veterinary immunogenic vaccines are the live attenuated, killed or inactivated bacteria, cell membrane components or toxoids [9,10]. Live attenuated immunogenic vaccines are very potent because they stimulate both cellular and humoral immune responses [11,12].
Innumerable Escherichia coli of animal origin are identified, which are of economic significance, likewise, cattle, sheep and goats are the carrier of enterohaemorrhagic E. coli, which are less pathogenic, and can spread to people by way of direct contact and through the contamination of foodstuff or portable drinking water, causing serious illness. The immunization of ruminants has been carried out for ages and is largely acknowledged as the most economical and maintainable process of monitoring E. coli infection in ruminants. Yet, only a limited number of E. coli vaccines are obtainable. Mucosal surfaces are the most important ingress for E. coli and thus mucosal immune responses function as the primary means of fortification. Largely contemporary vaccination processes are done by parenteral administration and merely limited number of E. coli vaccines are inoculated via mucosal itinerary, due to its decreased efficacy. Nevertheless, aiming at maximal mucosal partitions to stimulate defensive immunity at both mucosal compartments and systemic site epitomises a prodigious task. Enormous determinations are involved in order to improve on novel mucosal E. coli vaccines candidate by choosing apposite antigens with potent immunogenicity, manipulating novel mucosal itineraries of inoculation and choosing immune-inducing adjuvants. The target of E. coli mucosal vaccines is to stimulate a comprehensive, effective and defensive immunity by specifically counteracting the antibodies at mucosal linings and by the stimulation of cellular immunity. Furthermore, effective E. coli mucosal vaccine would make vaccination measures stress-free and appropriate for large number of inoculation. On account of contemporary advancement in proteomics, metagenomics, metabolomics and transcriptomics research, a comprehensive appraisal of the immeasurable genes and proteins that were divulged by a bacterium is now in easy reach. Moreover, there exist marvellous prospects in this bourgeoning technologies in comprehending the host bacteria affiliation. Accordingly, the flourishing knowledge could massively guarantee to the progression of immunogenic vaccines against E. coli infections in both humans and animals. This review highlight and expounds on the current prominence of mucosal and systemic immunogenic vaccines for the prevention of E. coli infections in ruminants.
Stabilization of a chimeric malaria antigen in separation and purification through efficient inhibition of protease activity by imidazole
2018, Process Biochemistry
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Hence, several multistage and multi-epitope vaccine candidates have been constructed which have shown good protection against malaria invasion [18,19]. Such chimeric subunit vaccines are generally expressed by recombinant host cells [20,21]. Various expression systems including E.coli [22], yeast [19], baculovirus-infected insect cells [17], or transgenic plant [23] are used to produce these chimeric protein-based antigens of malaria.
A chimeric antigen M.RCAg-1 of Plasmodium falciparum expressed in Escherichia coli was previously demonstrated inhibiting the growth of malaria parasites in vitro, but its further development has been retarded by the antigen’s instability during the downstream process. In this study, it was definitely demonstrated the instability was caused by the susceptibility of M.RCAg-1 to metalloprotease(s) released from the disintegrated host cells. Interestingly, imidazole showed better inhibition effects on the degradation than EDTA. Hence, a purification procedure was successfully developed to produce M.RCAg-1 with a purity of up to 95% and an overall recovery of nearly 600 mg/L culture. When performed this protocol following the Good Manufacturing Practice regulations, the endotoxin level, the host protein content and residual DNA level, all met the FDA standards. MALDI-TOF MS demonstrated a consistent molecular weight with the theoretical value and CD revealed a mainly disordered random coil secondary structure. Immunizing mice with M.RCAg-1 with Freund’s adjuvant elicited high levels of specific antibodies. Moreover, M.RCAg-1 itself could be stable at 4 °C for up to 6 months. Our results would provide an efficient and robust protocol for the large-scale production of M.RCAg-1 which would warrant the further development of this promising malaria vaccine candidate.

View all citing articles on Scopus

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Recombinant bacterial vaccines

Highlights

Introduction

Section snippets

Recombinant subunit vaccines

Recombinant bacterial strains

Vaccines based on protein structure

Conclusions

References and recommended reading

Lancet

Vaccine

Vaccine

Pediatr Infect Dis J

J Immunol

Clin Vaccine Immunol

JAMA

Vaccine

Int J Cancer

Hum Vaccin

Vaccine

Vaccine

Proc Natl Acad Sci USA

Sci Transl Med

Proc Natl Acad Sci USA

Microb Cell Fact

The development of vaccines: how the past led to the future

Nat Rev Microbiol

Mutants of pertussis toxin suitable for vaccine development

Science

Safety, reactogenicity and immunogenicity of a recombinant protective antigen anthrax vaccine given to healthy adults

Hum Vaccin

Phase I study of safety and immunogenicity of an Escherichia coli-derived recombinant protective antigen (rPA) vaccine to prevent anthrax in adults

PLoS ONE

Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing

Science

A universal vaccine for serogroup B meningococcus

Proc Natl Acad Sci USA

Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy

Clin Infect Dis

Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates

Clin Vaccine Immunol

Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study

Lancet