Development and Preclinical Evaluation of a Trivalent, Formalin-Inactivated Shigella Whole-Cell Vaccine

ABSTRACTStudies were undertaken to manufacture a multivalentShigellainactivated whole-cell vaccine that is safe, effective, and inexpensive. By using several formalin concentrations, temperatures, and incubation periods, an optimized set of inactivation conditions was established forShigella flexneri2a,S. sonnei, andS. flexneri3a to produce inactivated whole cells expressing a full repertoire of Ipa proteins and lipopolysaccharide (LPS). The inactivation conditions selected were treatment with 0.2% formalin (S. flexneri2a and 3a) or 0.6% formalin (S. sonnei) for 48 h at 25°C. Vaccine formulations prepared under different inactivation conditions, in different doses (10E5, 10E7, and 10E9 cells), and with or without the inclusion of double-mutant heat-labile toxin (dmLT) were evaluated in mice. Two intranasal immunizations with ≥10E7 inactivated whole cells resulted in high levels of anti-Invaplex and moderate levels of LPS-specific IgG and IgA in serum and in lung and intestinal wash samples. Addition of dmLT to the vaccine formulations did not significantly enhance humoral immunogenicity. Minimal humoral responses for IpaB, IpaC, or IpaD were detected after immunization with inactivated wholeShigellacells regardless of the vaccine inactivation conditions. In guinea pigs, monovalent formulations ofS. flexneri2a of 3a orS. sonneiconsisting of 10E8, 10E9, or 10E10 cells were protective in a keratoconjunctivitis assay. A trivalent formulation provided protection against all three serotypes (S. flexneri2a,P= 0.018;S. flexneri3a,P= 0.04;S. sonnei,P< 0.0001). The inactivatedShigellawhole-cell vaccine approach incorporates an uncomplicated manufacturing process that is compatible with multivalency and the future development of a broadly protectiveShigellavaccine.

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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.

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Antibody Responses to Bordetella pertussis Fim2 or Fim3 following Immunization with a Whole-Cell, Two-Component, or Five-Component Acellular Pertussis Vaccine and following Pertussis Disease in Children in Sweden in 1997 and 2007

Clinical and Vaccine Immunology ◽

10.1128/cvi.00641-13 ◽

2013 ◽

Vol 21 (2) ◽

pp. 165-173 ◽

Cited By ~ 9

Author(s):

Hans Hallander ◽

Abdolreza Advani ◽

Frances Alexander ◽

Lennart Gustafsson ◽

Margaretha Ljungman ◽

...

Keyword(s):

Pertussis Vaccine ◽

Bordetella Pertussis ◽

Geometric Mean ◽

Acellular Pertussis Vaccine ◽

Antibody Responses ◽

Cell Vaccine ◽

Whole Cell ◽

Content Type ◽

Two Component ◽

Whole Cell Vaccine

ABSTRACTBordetella pertussisfimbriae (Fim2 and Fim3) are components of a five-component acellular pertussis vaccine (diphtheria–tetanus–acellular pertussis vaccine [DTaP5]), and antibody responses to fimbriae have been associated with protection. We analyzed the IgG responses to individual Fim2 and Fim3 in sera remaining from a Swedish placebo-controlled efficacy trial that compared a whole-cell vaccine (diphtheria-tetanus-whole-cell pertussis vaccine [DTwP]), a two-component acellular pertussis vaccine (DTaP2), and DTaP5. One month following three doses of the Fim-containing vaccines (DTwP or DTaP5), anti-Fim2 geometric mean IgG concentrations were higher than those for anti-Fim3, with a greater anti-Fim2/anti-Fim3 IgG ratio elicited by DTaP5. We also determined the responses in vaccinated children following an episode of pertussis. Those who received DTaP5 showed a large rise in anti-Fim2 IgG, reflecting the predominant Fim2 serotype at the time. In contrast, those who received DTwP showed an equal rise in anti-Fim2 and anti-Fim3 IgG concentrations, indicating that DTwP may provide a more efficient priming effect for a Fim3 response following contact withB. pertussis. Anti-Fim2 and anti-Fim3 IgG concentrations were also determined in samples from two seroprevalence studies conducted in Sweden in 1997, when no pertussis vaccine was used and Fim2 isolates predominated, and in 2007, when either DTaP2 or DTaP3 without fimbriae was used and Fim3 isolates predominated. Very similar distributions of anti-Fim2 and anti-Fim3 IgG concentrations were obtained in 1997 and 2007, except that anti-Fim3 concentrations in 1997 were lower. This observation, together with the numbers of individuals with both anti-Fim2 and anti-Fim3 IgG concentrations, strongly suggests thatB. pertussisexpresses both Fim2 and Fim3 during infection.

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Killed but Metabolically Active Leishmania infantum as a Novel Whole-Cell Vaccine for Visceral Leishmaniasis

Clinical and Vaccine Immunology ◽

10.1128/cvi.05660-11 ◽

2012 ◽

Vol 19 (4) ◽

pp. 490-498 ◽

Cited By ~ 22

Author(s):

Kevin W. Bruhn ◽

Ron Birnbaum ◽

Jacquelyn Haskell ◽

Veena Vanchinathan ◽

Stephanie Greger ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Parasitic Infection ◽

Cell Vaccine ◽

Vaccine Strategy ◽

Whole Cell ◽

Content Type ◽

Whole Cell Vaccine

ABSTRACTThere are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here, we describe a novel whole-cell vaccine approach usingLeishmania infantum chagasipromastigotes treated with the psoralen compound amotosalen (S-59) and low doses of UV A radiation. This treatment generates permanent, covalent DNA cross-links within parasites and results inLeishmaniaorganisms termed killed but metabolically active (KBMA). In this report, we characterize thein vitrogrowth characteristics of both KBMAL. majorand KBMAL. infantum chagasi. Concentrations of S-59 that generate optimally attenuated parasites were identified. Like liveL. infantum chagasi, KBMAL. infantum chagasiparasites were able to initially enter liver cellsin vivoafter intravenous infection. However, whereas liveL. infantum chagasiinfection leads to hepatosplenomegaly in mice after 6 months, KBMAL. infantum chagasiparasites were undetectable in the organs of mice at this time point.In vitro, KBMAL. infantum chagasiretained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMAL. infantum chagasicorrelated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either liveL. infantum chagasior KBMAL. infantum chagasidisplayed similar cytokine patternsin vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoanL. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens.

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Whole Cell Vaccine

10.32388/qojyc0 ◽

2020 ◽

Author(s):

Keyword(s):

Cell Vaccine ◽

Whole Cell ◽

Whole Cell Vaccine

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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

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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

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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.

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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.

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