Coxiella burnetii Whole Cell Vaccine Produces a Th1 Delayed-Type Hypersensitivity Response in a Novel Sensitized Mouse Model

Q-VAX®, a whole cell, formalin-inactivated vaccine, is the only vaccine licensed for human use to protect against Coxiella burnetii, the cause of Q fever. Although this vaccine provides long-term protection, local and systemic reactogenic responses are common in previously sensitized individuals which prevents its use outside of Australia. Despite the importance of preventing these adverse reactions to develop widely accepted, novel vaccines against C. burnetii, little is understood about the underlying cellular mechanisms. This is mostly attributed to the use of a guinea pig reactogenicity model where complex cellular analysis is limited. To address this, we compared three different mouse strains develop a model of C. burnetii whole cell vaccine reactogenic responses. SKH1 and C57Bl/6, but not BALBc mice, develop local granulomatous reactions after either infection- or vaccine-induced sensitization. We evaluated local and systemic responses by measuring T cell populations from the vaccination site and spleen during elicitation using flow cytometry. Local reaction sites showed influx of IFNγ+ and IL17a+ CD4 T cells in sensitized mice compared with controls and a reduction in IL4+ CD4 T cells. Additionally, sensitized mice showed a systemic response to elicitation by an increase in IFNγ+ and IL17a+ CD4 T cells in the spleen. These results indicate that local and systemic C. burnetii reactogenic responses are consistent with a Th1 delayed-type hypersensitivity. Our experiments provide insights into the pathophysiology of C. burnetii whole cell vaccine reactogenicity and demonstrate that C57Bl/6 and SKH1 mice can provide a valuable model for evaluating the reactogenicity of novel C. burnetii vaccine candidates.

Download Full-text

Chemokine Receptor 7 Is Essential for Coxiella burnetii Whole-Cell Vaccine-Induced Cellular Immunity but Dispensable for Vaccine-Mediated Protective Immunity

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz146 ◽

2019 ◽

Vol 220 (4) ◽

pp. 624-634

Author(s):

Chen Chen ◽

Erin J van Schaik ◽

Anthony E Gregory ◽

Adam Vigil ◽

Phillip L Felgner ◽

...

Keyword(s):

Coxiella Burnetii ◽

Cellular Immunity ◽

Protective Immunity ◽

Cell Vaccine ◽

Specific Antibody Response ◽

Whole Cell ◽

Humoral Immune ◽

Whole Cell Vaccine ◽

Secondary Lymphoid Organs ◽

Dc Maturation

Abstract Background Protective immunity against Coxiella burnetii infection is conferred by vaccination with virulent (PI-WCV), but not avirulent (PII-WCV) whole-cell inactivated bacterium. The only well-characterized antigenic difference between virulent and avirulent C. burnetii is they have smooth and rough lipopolysaccharide (LPS), respectively. Methods Mice were vaccinated with PI-WCV and PII-WCV. Humoral and cellular responses were evaluated using protein chip microarrays and ELISpots, respectively. Dendritic cell (DC) maturation after stimulation with PI-WVC and PII-WVC was evaluated using flow cytometry. Vaccine-challenge studies were performed to validate the importance of the receptor CCR7. Results Other than specific antibody response to PI-LPS, similar antibody profiles were observed but IgG titers were significantly higher after vaccination with PI-WCV. Furthermore, higher frequency of antigen-specific CD4+ T cells was detected in mice immunized with PI-WCV. PI-WCV–stimulated DCs displayed significantly higher levels of CCR7 and migratory ability to secondary lymphoid organs. Challenge-protection studies in wild-type and CCR7-deficient mice confirmed that CCR7 is critical for PI-WCV–induced cellular immunity. Conclusions PI-WVC stimulates protective immunity to C. burnetii in mice through stimulation of migratory behavior in DCs for protective cellular immunity. Additionally, the humoral immune response to LPS is an important component of protective immunity.

Download Full-text

Subunit Vaccines Using TLR Triagonist Combination Adjuvants Provide Protection Against Coxiella burnetii While Minimizing Reactogenic Responses

Frontiers in Immunology ◽

10.3389/fimmu.2021.653092 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alycia P. Fratzke ◽

Sharon Jan ◽

Jiin Felgner ◽

Li Liang ◽

Rie Nakajima ◽

...

Keyword(s):

Coxiella Burnetii ◽

Q Fever ◽

Protective Efficacy ◽

Cell Vaccine ◽

Protein Subunit ◽

Subunit Vaccines ◽

Whole Cell ◽

Vaccine Candidates ◽

Route Of Transmission ◽

Whole Cell Vaccine

Q fever is caused by the obligate intracellular bacterium, Coxiella burnetii, a designated potential agent of bioterrorism because of its route of transmission, resistance to disinfectants, and low infectious dose. The only vaccine licensed for human use is Q-VAX® (Seqirus, licensed in Australia), a formalin-inactivated whole-cell vaccine, which produces severe local and systemic reactogenic responses in previously sensitized individuals. Accordingly, the U.S. Food and Drug Administration and other regulatory bodies around the world, have been reluctant to approve Q-VAX for widespread use. To obviate these adverse reactions, we prepared recombinant protein subunit vaccine candidates containing purified CBU1910, CBU0307, CBU0545, CBU0612, CBU0891, and CBU1398 proteins and TLR triagonist adjuvants. TLR triagonist adjuvants combine different TLR agonists to enhance immune responses to vaccine antigens. We tested both the protective efficacy and reactogenicity of our vaccine candidates in Hartley guinea pigs using intratracheal infection with live C. burnetii. While all of our candidates showed varying degrees of protection during challenge, local reactogenic responses were significantly reduced for one of our vaccine candidates when compared with a formalin-inactivated whole-cell vaccine. Our findings show that subunit vaccines combined with novel TLR triagonist adjuvants can generate protective immunity to C. burnetii infection while reducing reactogenic responses.

Download Full-text

Whole Cell Vaccine

10.32388/qojyc0 ◽

2020 ◽

Author(s):

Keyword(s):

Cell Vaccine ◽

Whole Cell ◽

Whole Cell Vaccine

Download Full-text

Faculty Opinions recommendation of A Phase 1 Randomized, Placebo-controlled, Observer-blinded Trial to Evaluate the Safety and Immunogenicity of Inactivated Streptococcus pneumoniae Whole-cell Vaccine in Adults.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737155235.793573973 ◽

2020 ◽

Author(s):

Charles Feldman

Keyword(s):

Streptococcus Pneumoniae ◽

Phase 1 ◽

Cell Vaccine ◽

Whole Cell ◽

Whole Cell Vaccine ◽

Blinded Trial

Download Full-text

Contributions of lipopolysaccharide and the type IVB secretion system to Coxiella burnetii vaccine efficacy and reactogenicity

npj Vaccines ◽

10.1038/s41541-021-00296-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Carrie M. Long ◽

Paul A. Beare ◽

Diane C. Cockrell ◽

Jonathan Fintzi ◽

Mahelat Tesfamariam ◽

...

Keyword(s):

Phase I ◽

Coxiella Burnetii ◽

Vaccine Efficacy ◽

Q Fever ◽

Secretion System ◽

Cell Vaccine ◽

Post Vaccination ◽

Whole Cell Vaccine ◽

Type Ivb Secretion ◽

Type Ivb Secretion System

AbstractCoxiella burnetii is the bacterial causative agent of the zoonosis Q fever. The current human Q fever vaccine, Q-VAX®, is a fixed, whole cell vaccine (WCV) licensed solely for use in Australia. C. burnetii WCV administration is associated with a dermal hypersensitivity reaction in people with pre-existing immunity to C. burnetii, limiting wider use. Consequently, a less reactogenic vaccine is needed. Here, we investigated contributions of the C. burnetii Dot/Icm type IVB secretion system (T4BSS) and lipopolysaccharide (LPS) in protection and reactogenicity of fixed WCVs. A 32.5 kb region containing 23 dot/icm genes was deleted in the virulent Nine Mile phase I (NMI) strain and the resulting mutant was evaluated in guinea pig models of C. burnetii infection, vaccination-challenge, and post-vaccination hypersensitivity. The NMI ∆dot/icm strain was avirulent, protective as a WCV against a robust C. burnetii challenge, and displayed potentially altered reactogenicity compared to NMI. Nine Mile phase II (NMII) strains of C. burnetii that produce rough LPS, were similarly tested. NMI was significantly more protective than NMII as a WCV; however, both vaccines exhibited similar reactogenicity. Collectively, our results indicate that, like phase I LPS, the T4BSS is required for full virulence by C. burnetii. Conversely, unlike phase I LPS, the T4BSS is not required for vaccine-induced protection. LPS length does not appear to contribute to reactogenicity while the T4BSS may contribute to this response. NMI ∆dot/icm represents an avirulent phase I strain with full vaccine efficacy, illustrating the potential of genetically modified C. burnetii as improved WCVs.

Download Full-text

Bordetella pertussis outer membrane vesicle vaccine confers equal efficacy in mice with milder inflammatory responses compared to a whole-cell vaccine

Scientific Reports ◽

10.1038/srep38240 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 23

Author(s):

René H. M. Raeven ◽

Jolanda Brummelman ◽

Jeroen L. A. Pennings ◽

Larissa van der Maas ◽

Wichard Tilstra ◽

...

Keyword(s):

Outer Membrane ◽

Bordetella Pertussis ◽

Inflammatory Responses ◽

Membrane Vesicle ◽

Cell Vaccine ◽

Outer Membrane Vesicle ◽

Whole Cell ◽

Whole Cell Vaccine ◽

Equal Efficacy

Download Full-text

Primary Immunization of Infants With an Acellular Pertussis Vaccine in a Double-Blind Randomized Clinical Trial

PEDIATRICS ◽

10.1542/peds.82.3.293 ◽

1988 ◽

Vol 82 (3) ◽

pp. 293-299

Author(s):

Margareta Blennow ◽

Marta Granström ◽

Eva Jäätmaa ◽

Patrick Olin

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Pertussis Vaccine ◽

Acellular Pertussis Vaccine ◽

Cell Vaccine ◽

Primary Immunization ◽

Double Blind ◽

Whole Cell ◽

Whole Cell Vaccine ◽

Acellular Vaccine

The rate of adverse reactions and the immunogenicity of a two-component acellular pertussis vaccine as compared with a plain whole-cell vaccine and a placebo were evaluated for primary immunization in 319 6-month-old infants in a double-blind randomized clinical trial. The acellular vaccine produced few and mild systemic and local reactions. Fever (≥38°C) occurred in 6% to 8% of acellular vaccinees as opposed to 25% to 37% of whole-cell vaccinees. Redness (≥1 cm) appeared in 2% to 13% of the acellular vaccine and 24% to 32% of the whole-cell vaccine recipients. Antibody response to pertussis toxin measured in a neutralization test was obtained in 97% to 100% of the infants receiving either two or three doses of the acellular vaccine as compared to 59% after three doses of whole-cell vaccine.

Download Full-text

PERTUSSIS INCIDENCE AND THE EFFECT OF REVACCINATION OF PRESCHOOL AND SCHOOL CHILDREN

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-2018-3-284-294 ◽

2018 ◽

Vol 8 (3) ◽

pp. 284-294 ◽

Cited By ~ 1

Author(s):

А. M. Kostinov ◽

M. P. Kostinov

Keyword(s):

Favorable Effect ◽

Cell Vaccine ◽

School Age ◽

Pertussis Infection ◽

Whole Cell ◽

Number Of Factors ◽

Foreign Countries ◽

Incidence And Mortality ◽

Whole Cell Vaccine ◽

Cytomegalovirus Infections

The review is devoted to the analysis of pertussis incidence of children in the age group of 5–7, as well as strategies of DTP immunization with the help of the drugs in foreign countries. Mass vaccination against pertussis began in the middle of the 20th century, which contributed to a reduction in incidence and mortality rate from this infection. However, in the last decade, there has been an opposite tendency of increasing incidence of patients among children under school age, school age and adults. Atypical forms of the disease and complications due to ARVI, respiratory mycoplasmosis and cytomegalovirus infections are described in the review. Various strategies for the use of whole-cell and acellular pertussis vaccines as part of DTP drugs are described, as well as the epidemiological effect of introducing an additional booster dose of vaccine to children under school age. The expediency of revaccination of children aged 6–7 in Russia is argued, which can help to reduce the overall incidence of pertussis. The research materials related to the study of the properties of acellular anti-pertussis vaccine, such as immunogenicity and safety in comparison with whole-cell vaccine, are analyzed. The main drugs and their composition, which are used to vaccinate children against pertussis, are described in the review. It is assumed, that the increase in the incidence among children and teenagers, with the appearance of atypical forms of pertussis, is associated with a number of factors, such as the spread of new genotypes of Bordetella pertussis bacterium, emerged from mutations, as well as short duration of immunity after vaccination with acellular drugs, in comparison with whole-cell, and the use of more modern methods of detecting the pathogen. The mechanisms of the immune response due to different types of pertussis vaccines are also reviewed. It is concluded, that revaccination of children aged 6–7 with an additional fifth dose of an acellular vaccine against pertussis, as part of the DTaP instead of the Td drug, which is regulated in the National Calendar of preventive vaccinations, will have a favorable effect on the epidemic situation with pertussis infection in Russia.

Download Full-text

A Self-Assembling Whole-Cell Vaccine Antigen Presentation Platform

Journal of Bacteriology ◽

10.1128/jb.00752-17 ◽

2018 ◽

Vol 200 (15) ◽

Cited By ~ 1

Author(s):

Julie Liao ◽

Daniel R. Smith ◽

Jóhanna Brynjarsdóttir ◽

Paula I. Watnick

Keyword(s):

Vibrio Cholerae ◽

Bacterial Biofilm ◽

Cell Vaccine ◽

Secreted Protein ◽

Proof Of Concept ◽

Whole Cell ◽

Content Type ◽

Self Assembling ◽

Whole Cell Vaccine ◽

Common Infection

ABSTRACTDiarrhea is the most common infection in children under the age of 5 years worldwide. In spite of this, only a few vaccines to treat infectious diarrhea exist, and many of the available vaccines are sparingly and sporadically administered. Major obstacles to the development and widespread implementation of vaccination include the ease and cost of production, distribution, and delivery. Here we present a novel, customizable, and self-assembling vaccine platform that exploits theVibrio choleraebacterial biofilm matrix for antigen presentation. We use this technology to create a proof-of-concept, live-attenuated whole-cell vaccine that is boosted by spontaneous association of a secreted protein antigen with the cell surface. Sublingual administration of this live-attenuated vaccine to mice confers protection againstV. choleraechallenge and elicits the production of antigen-specific IgA in stool. The platform presented here enables the development of antigen-boosted vaccines that are simple to produce and deliver, addressing many of the obstacles to vaccination against diarrheal diseases. This may also serve as a paradigm for the development of broadly protective biofilm-based vaccines against other mucosal infections.IMPORTANCEDiarrheal disease is the most common infection afflicting children worldwide. In resource-poor settings, these infections are correlated with cognitive delay, stunted growth, and premature death. With the development of efficacious, affordable, and easily administered vaccines, such infections could be prevented. While a major focus of research on biofilms has been their elimination, here we harness the bacterial biofilm to create a customizable platform for cost-effective, whole-cell mucosal vaccines that self-incorporate secreted protein antigens. We use this platform to develop a sublingually administered live-attenuated prototype vaccine based onVibrio cholerae. This serves not only as a proof of concept for a multivalent vaccine against common bacterial enteric pathogens but also as a paradigm for vaccines utilizing other bacterial biofilms to target mucosal infections.

Download Full-text