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Vaccines
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Next-Generation Pertussis Vaccines
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Next-Generation Pertussis Vaccines

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines against Infectious Diseases".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 42143

Special Issue Editors

Prof. Kingston Mills

E-Mail Website
Guest Editor
Trinity Biomedical Sciences Institute, Dublin, Ireland
Interests: CD4 T cells; vaccines; adjuvants; immunity to Bordetella pertussis
Dr. F. Heath Damron

E-Mail Website
Guest Editor
Department of Microbiology, Immunology & Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA
Interests: bordetella pertussis pathogenesis; pertussis vaccine development; therapeutic antibodies

Special Issue Information

Dear Colleagues,

The incidence of pertussis is increasing in many countries, especially those using acellular pertussis (aP) vaccines, and this has resulted in renewed research focus on a disease that was once thought to be on the way out. Pertussis is a life-threatening disease in infants characterized caused by Bordetella pertussis, a Gram-negative obligate human pathogen that colonizes the upper respiratory tract. B. pertussis was first cultured by Jules Bordet and Octave Gengou in 1906. Whole cell pertussis (wP) vaccines were developed in the 1930s and 1940s and by the 1970s had decreased incidence of the disease down to the point that clinicians and scientists believed it could be eradicated. However, wP vaccines were reactogenic, and media coverage on adverse reactions associated with their use led to public concern about vaccine safety. In Japan, the wP vaccine was removed from use, and overall incidence of pertussis rose dramatically. Yuji Sato and Hiroko Sato developed an “adsorbed purified pertussis vaccine" which contained formaldehyde detoxified pertussis toxin (PT) and filamentous haemagglutinin (FHA), and in 1981, the first aP vaccine was being used in Japan.

aP vaccines were developed in the US and Europe in the 1980s–1990s, and the DTaP infant vaccine series was implemented in the late 1990s or early 2000s. However, in recent years, the incidence of pertussis in the US and Europe has been increasing. In 2012, the US experienced the highest number of cases in 50 years, 50-fold over the lowest incidence back in 1976 during the wP vaccine era. There are several possible reasons for the return of pertussis, including: (1) waning of protective immunity following immunization with aP vaccines, (2) evolution of strain due to vaccine-driven immune selection pressure, (3) a failure of aP vaccines to induce effective T cell response, and (4) the inability of aP vaccines to block nasal colonization and transmission of B. pertussis. Epidemiology and genomics studies have revealed considerable evolution of the pathogen. The baboon model of pertussis has demonstrated that aP vaccines do not protect against transmission and asymptomatic infection. Studies in the mouse model have shown that the aP vaccine fails to generate protective T cells, especially those in the respiratory tissue that maintain long-term memory. In the US, the oldest acellular-only vaccinated population is currently 23 years of age, so we are at the point where a new generation of children will be born to acellular-only immunized parents. There is general agreement that we need to develop a “next generation” pertussis vaccine; however, there is no clear roadmap for their development, but it is clear that it must solve some of the issues with the current one. Since the solutions are not obvious, we would like to invite cutting-edge manuscripts for a Special Issue of Vaccines on ‘Next-Generation Pertussis Vaccines’. We invite authors to contribute original articles or reviews that address this public health concern.

We encourage submissions of manuscripts that investigate novel formulations that include the use of new antigens and adjuvants, or changes in routes of administration. Manuscripts that investigate the role of adjuvants and T cell responses to study the longevity of protection and waning vaccine immunity are also encouraged. In addition, we also welcome the submission of manuscripts investigating the use of preclinical models, platforms strategies, and clinical surrogate endpoints to better understand protection.

Prof. Kingston Mills
Dr. F. Heath Damron
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bordetella pertussis
  • Pertussis
  • Whooping cough
  • New pertussis antigens
  • New pertussis adjuvants
  • Change in routes of administration
  • Skewing of T cell responses
  • Overcoming waning aP vaccine-induced immunity
  • Novel Tdap formulations
  • Novel preclinical models of vaccine evaluation
  • Novel clinical trial strategies
  • Surrogate endpoints
  • Understanding vaccine-induced memory

Published Papers (8 papers)

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Research

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21 pages, 3462 KiB  
Article
Immunological Distinctions between Acellular and Whole-Cell Pertussis Immunizations of Baboons Persist for at Least One Year after Acellular Vaccine Boosting
by Leah E. Cole, Jinrong Zhang, Kristl M. Pacheco, Philippe Lhéritier, Natalie G. Anosova, Julie Piolat, Lingyi Zheng and Nathalie Reveneau
Vaccines 2020, 8(4), 729; https://doi.org/10.3390/vaccines8040729 - 02 Dec 2020
Cited by 7 | Viewed by 3026
Abstract
While both whole-cell (wP) and acellular pertussis (aP) vaccines have been highly effective at reducing the global pertussis disease burden, there are concerns that compared to wP vaccination, the immune responses to aP vaccination may wane more rapidly. To gain insights into the [...] Read more.
While both whole-cell (wP) and acellular pertussis (aP) vaccines have been highly effective at reducing the global pertussis disease burden, there are concerns that compared to wP vaccination, the immune responses to aP vaccination may wane more rapidly. To gain insights into the vaccine elicited immune responses, pre-adult baboons were immunized with either aP or wP vaccines, boosted with an aP vaccine, and observed over a nearly two-year period. Priming with a wP vaccine elicited a more Th17-biased response than priming with aP, whereas priming with an aP vaccine led to a more Th2-biased response than priming with wP. These differences were maintained after aP vaccine boost immunizations. Compared to aP, animals primed with a wP vaccine exhibited greater numbers of pertussis specific memory B cells. While aP and wP vaccine priming initially elicited similar levels of anti-pertussis toxin antibody, titers declined more rapidly in aP vaccine primed animals leading to a 4-fold difference. Both wP and aP vaccine immunization could induce serum bactericidal activity (SBA); however, only one wP vaccine immunization was required to elicit SBA while multiple aP vaccine immunizations were required to elicit lower, less durable SBA titers. In conclusion, when compared to aP vaccine, priming with wP vaccine elicits distinct cellular and humoral immune responses that persist after aP vaccine boosting. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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21 pages, 3913 KiB  
Article
Innate and Adaptive Immune Responses against Bordetella pertussis and Pseudomonas aeruginosa in a Murine Model of Mucosal Vaccination against Respiratory Infection
by Catherine B. Blackwood, Emel Sen-Kilic, Dylan T. Boehm, Jesse M. Hall, Melinda E. Varney, Ting Y. Wong, Shelby D. Bradford, Justin R. Bevere, William T. Witt, F. Heath Damron and Mariette Barbier
Vaccines 2020, 8(4), 647; https://doi.org/10.3390/vaccines8040647 - 03 Nov 2020
Cited by 13 | Viewed by 4894
Abstract
Whole cell vaccines are frequently the first generation of vaccines tested for pathogens and can inform the design of subsequent acellular or subunit vaccines. For respiratory pathogens, administration of vaccines at the mucosal surface can facilitate the generation of a localized mucosal immune [...] Read more.
Whole cell vaccines are frequently the first generation of vaccines tested for pathogens and can inform the design of subsequent acellular or subunit vaccines. For respiratory pathogens, administration of vaccines at the mucosal surface can facilitate the generation of a localized mucosal immune response. Here, we examined the innate and vaccine-induced immune responses to infection by two respiratory pathogens: Bordetella pertussis and Pseudomonas aeruginosa. In a model of intranasal administration of whole cell vaccines (WCVs) with the adjuvant curdlan, we examined local and systemic immune responses following infection. These studies showed that intranasal vaccination with a WCV led to a reduction of the bacterial burden in the airways of animals infected with the respective pathogen. However, there were unique changes in the cytokines produced, cells recruited, and inflammation at the site of infection. Both mucosal vaccinations induced antibodies that bind the target pathogen, but linear regression and principal component analysis revealed that protection from these pathogens is not solely related to antibody titer. Protection from P. aeruginosa correlated to a reduction in lung weight, blood lymphocytes and neutrophils, and the cytokines IL-6, TNF-α, KC/GRO, and IL-10, and promotion of serum IgG antibodies and the cytokine IFN-γ in the lung. Protection from B. pertussis infection correlated strongly with increased anti-B-pertussis serum IgG antibodies. These findings reveal valuable correlates of protection for mucosal vaccination that can be used for further development of both B. pertussis and P. aeruginosa vaccines. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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20 pages, 2327 KiB  
Article
Shortening the Lipid A Acyl Chains of Bordetella pertussis Enables Depletion of Lipopolysaccharide Endotoxic Activity
by Jesús Arenas, Elder Pupo, Coen Phielix, Dionne David, Afshin Zariri, Alla Zamyatina, Jan Tommassen and Peter van der Ley
Vaccines 2020, 8(4), 594; https://doi.org/10.3390/vaccines8040594 - 09 Oct 2020
Cited by 12 | Viewed by 3676
Abstract
Whooping cough, or pertussis, is an acute respiratory infectious disease caused by the Gram-negative bacterium Bordetella pertussis. Whole-cell vaccines, which were introduced in the fifties of the previous century and proved to be effective, showed considerable reactogenicity and were replaced by subunit vaccines [...] Read more.
Whooping cough, or pertussis, is an acute respiratory infectious disease caused by the Gram-negative bacterium Bordetella pertussis. Whole-cell vaccines, which were introduced in the fifties of the previous century and proved to be effective, showed considerable reactogenicity and were replaced by subunit vaccines around the turn of the century. However, there is a considerable increase in the number of cases in industrialized countries. A possible strategy to improve vaccine-induced protection is the development of new, non-toxic, whole-cell pertussis vaccines. The reactogenicity of whole-cell pertussis vaccines is, to a large extent, derived from the lipid A moiety of the lipopolysaccharides (LPS) of the bacteria. Here, we engineered B. pertussis strains with altered lipid A structures by expressing genes for the acyltransferases LpxA, LpxD, and LpxL from other bacteria resulting in altered acyl-chain length at various positions. Whole cells and extracted LPS from the strains with shorter acyl chains showed reduced or no activation of the human Toll-like receptor 4 in HEK-Blue reporter cells, whilst a longer acyl chain increased activation. Pyrogenicity studies in rabbits confirmed the in vitro assays. These findings pave the way for the development of a new generation of whole-cell pertussis vaccines with acceptable side effects. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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16 pages, 1287 KiB  
Article
Manufacture of a Stable Lyophilized Formulation of the Live Attenuated Pertussis Vaccine BPZE1
by Marcel Thalen, Anne-Sophie Debrie, Loic Coutte, Dominique Raze, Ken Solovay, Keith Rubin, Nathalie Mielcarek and Camille Locht
Vaccines 2020, 8(3), 523; https://doi.org/10.3390/vaccines8030523 - 13 Sep 2020
Cited by 5 | Viewed by 2803
Abstract
Current pertussis vaccines protect against disease, but not against colonization by and transmission of Bordetella pertussis, whereas natural infection protects against both. The live attenuated vaccine BPZE1 was developed to mimic immunogenicity of natural infection without causing disease, and in preclinical models [...] Read more.
Current pertussis vaccines protect against disease, but not against colonization by and transmission of Bordetella pertussis, whereas natural infection protects against both. The live attenuated vaccine BPZE1 was developed to mimic immunogenicity of natural infection without causing disease, and in preclinical models protected against pertussis disease and B. pertussis colonization after a single nasal administration. Phase 1 clinical studies showed that BPZE1 is safe and immunogenic in humans when administered as a liquid formulation, stored at ≤−70 °C. Although BPZE1 is stable for two years at ≤−70 °C, a lyophilized formulation stored at ≥5 °C is required for commercialization. The development of a BPZE1 drug product, filled and lyophilized directly in vials, showed that post-lyophilization survival of BPZE1 depended on the time of harvest, the lyophilization buffer, the time between harvest and lyophilization, as well as the lyophilization cycle. The animal component-free process, well defined in terms of harvest, processing and lyophilization, resulted in approximately 20% survival post-lyophilization. The resulting lyophilized drug product was stable for at least two years at −20 °C ± 10 °C, 5 °C ± 3 °C and 22.5 °C ± 2.5 °C and maintained its vaccine potency, as evaluated in a murine protection assay. This manufacturing process thus enables further clinical and commercial development of BPZE1. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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22 pages, 2719 KiB  
Article
The Role of Virulence Proteins in Protection Conferred by Bordetella pertussis Outer Membrane Vesicle Vaccines
by René H. M. Raeven, Naomi van Vlies, Merijn L. M. Salverda, Larissa van der Maas, Joost P. Uittenbogaard, Tim H. E. Bindels, Jolanda Rigters, Lisa M. Verhagen, Sabine Kruijer, Elly van Riet, Bernard Metz and Arno A. J. van der Ark
Vaccines 2020, 8(3), 429; https://doi.org/10.3390/vaccines8030429 - 30 Jul 2020
Cited by 10 | Viewed by 4244
Abstract
The limited protective immunity induced by acellular pertussis vaccines demands development of novel vaccines that induce broader and longer-lived immunity. In this study, we investigated the protective capacity of outer membrane vesicle pertussis vaccines (omvPV) with different antigenic composition in mice to gain [...] Read more.
The limited protective immunity induced by acellular pertussis vaccines demands development of novel vaccines that induce broader and longer-lived immunity. In this study, we investigated the protective capacity of outer membrane vesicle pertussis vaccines (omvPV) with different antigenic composition in mice to gain insight into which antigens contribute to protection. We showed that total depletion of virulence factors (bvg(-) mode) in omvPV led to diminished protection despite the presence of high antibody levels. Antibody profiling revealed overlap in humoral responses induced by vaccines in bvg(-) and bvg(+) mode, but the potentially protective responses in the bvg(+) vaccine were mainly directed against virulence-associated outer membrane proteins (virOMPs) such as BrkA and Vag8. However, deletion of either BrkA or Vag8 in our outer membrane vesicle vaccines did not affect the level of protection. In addition, the vaccine-induced immunity profile, which encompasses broad antibody and mixed T-helper 1, 2 and 17 responses, was not changed. We conclude that the presence of multiple virOMPs in omvPV is crucial for protection against Bordetella pertussis. This protective immunity does not depend on individual proteins, as their absence or low abundance can be compensated for by other virOMPs. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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23 pages, 9684 KiB  
Article
Uncovering Distinct Primary Vaccination-Dependent Profiles in Human Bordetella pertussis Specific CD4+ T-Cell Responses Using a Novel Whole Blood Assay
by Eleonora E. Lambert, Véronique Corbière, Jacqueline A. M. van Gaans-van den Brink, Maxime Duijst, Prashanna Balaji Venkatasubramanian, Elles Simonetti, Martijn Huynen, Dimitri D. Diavatopoulos, Pauline Versteegen, Guy A. M. Berbers, Françoise Mascart and Cécile A. C. M. van Els
Vaccines 2020, 8(2), 225; https://doi.org/10.3390/vaccines8020225 - 15 May 2020
Cited by 11 | Viewed by 2989
Abstract
To advance research and development of improved pertussis vaccines, new immunoassays are needed to qualify the outcome of Bordetella pertussis (Bp) specific CD4+ T-cell differentiation. Here, we applied a recently developed whole blood assay to evaluate Bp specific CD4+ T-cell responses. The assay [...] Read more.
To advance research and development of improved pertussis vaccines, new immunoassays are needed to qualify the outcome of Bordetella pertussis (Bp) specific CD4+ T-cell differentiation. Here, we applied a recently developed whole blood assay to evaluate Bp specific CD4+ T-cell responses. The assay is based on intracellular cytokine detection after overnight in vitro Bp antigen stimulation of diluted whole blood. We show for the first time that CD4+ T-cell memory of Th1, Th2, and Th17 lineages can be identified simultaneously in whole blood. Participants ranging from 7 to 70 years of age with different priming backgrounds of whole-cell pertussis (wP) and acellular pertussis (aP) vaccination were analyzed around an acellular booster vaccination. The assay allowed detection of low frequent antigen-specific CD4+ T-cells and revealed significantly elevated numbers of activated and cytokine-producing CD4+ T-cells, with a significant tendency to segregate recall responses based on primary vaccination background. A stronger Th2 response hallmarked an aP primed cohort compared to a wP primed cohort. In conclusion, analysis of Bp specific CD4+ T-cell responses in whole blood showed separation based on vaccination background and provides a promising tool to assess the quantity and quality of CD4+ T-cell responses induced by vaccine candidates. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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Review

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28 pages, 1861 KiB  
Review
Next-Generation Pertussis Vaccines Based on the Induction of Protective T Cells in the Respiratory Tract
by Caitlín Ní Chasaide and Kingston H.G. Mills
Vaccines 2020, 8(4), 621; https://doi.org/10.3390/vaccines8040621 - 21 Oct 2020
Cited by 25 | Viewed by 9858
Abstract
Immunization with current acellular pertussis (aP) vaccines protects against severe pertussis, but immunity wanes rapidly after vaccination and these vaccines do not prevent nasal colonization with Bordetella pertussis. Studies in mouse and baboon models have demonstrated that Th1 and Th17 responses are [...] Read more.
Immunization with current acellular pertussis (aP) vaccines protects against severe pertussis, but immunity wanes rapidly after vaccination and these vaccines do not prevent nasal colonization with Bordetella pertussis. Studies in mouse and baboon models have demonstrated that Th1 and Th17 responses are integral to protective immunity induced by previous infection with B. pertussis and immunization with whole cell pertussis (wP) vaccines. Mucosal Th17 cells, IL-17 and secretory IgA (sIgA) are particularly important in generating sustained sterilizing immunity in the nasal cavity. Current aP vaccines induce potent IgG and Th2-skewed T cell responses but are less effective at generating Th1 and Th17 responses and fail to prime respiratory tissue-resident memory T (TRM) cells, that maintain long-term immunity at mucosal sites. In contrast, a live attenuated pertussis vaccine, pertussis outer membrane vesicle (OMV) vaccines or aP vaccines formulated with novel adjuvants do induce cellular immune responses in the respiratory tract, especially when delivered by the intranasal route. An increased understanding of the mechanisms of sustained protective immunity, especially the role of respiratory TRM cells, will facilitate the development of next generation pertussis vaccines that not only protect against pertussis disease, but prevent nasal colonization and transmission of B. pertussis. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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16 pages, 652 KiB  
Review
Acellular Pertussis Vaccine Components: Today and Tomorrow
by Kalyan K. Dewan, Bodo Linz, Susan E. DeRocco and Eric T. Harvill
Vaccines 2020, 8(2), 217; https://doi.org/10.3390/vaccines8020217 - 13 May 2020
Cited by 29 | Viewed by 9735
Abstract
Pertussis is a highly communicable acute respiratory infection caused by Bordetella pertussis. Immunity is not lifelong after natural infection or vaccination. Pertussis outbreaks occur cyclically worldwide and effective vaccination strategies are needed to control disease. Whole-cell pertussis (wP) vaccines became available in [...] Read more.
Pertussis is a highly communicable acute respiratory infection caused by Bordetella pertussis. Immunity is not lifelong after natural infection or vaccination. Pertussis outbreaks occur cyclically worldwide and effective vaccination strategies are needed to control disease. Whole-cell pertussis (wP) vaccines became available in the 1940s but have been replaced in many countries with acellular pertussis (aP) vaccines. This review summarizes disease epidemiology before and after the introduction of wP and aP vaccines, discusses the rationale and clinical implications for antigen inclusion in aP vaccines, and provides an overview of novel vaccine strategies aimed at better combating pertussis in the future. Full article
(This article belongs to the Special Issue Next-Generation Pertussis Vaccines)
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