Waning Protection after Fifth Dose of Acellular Pertussis Vaccine in Children

Klein, Nicola P.; Bartlett, Joan; Rowhani-Rahbar, Ali; Fireman, Bruce; Baxter, Roger

doi:10.1056/nejmoa1200850

Cited by 487 publications

(366 citation statements)

References 19 publications

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“…Although some first-generation acellular vaccines had poor immunity and efficacy, double-blinded clinical trials and field-efficacy studies for the US-licensed acellular vaccines estimated the short-term efficacy to be excellent: ∼85% after three doses and 98% after five doses (28)(29)(30). However, recent cohort and case-control studies concluded that 5 y following the fifth aP dose, children are fourfold to 15-fold more likely to acquire pertussis compared with within the first year, consistent with waning aP immunity (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model

Warfel

Zimmerman

Merkel

2013

Proc. Natl. Acad. Sci. U.S.A.

534

531

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Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis. Pertussis rates in the United States have been rising and reached a 50-y high of 42,000 cases in 2012. Although pertussis resurgence is not completely understood, we hypothesize that current acellular pertussis (aP) vaccines fail to prevent colonization and transmission. To test our hypothesis, infant baboons were vaccinated at 2, 4, and 6 mo of age with aP or whole-cell pertussis (wP) vaccines and challenged with B. pertussis at 7 mo. Infection was followed by quantifying colonization in nasopharyngeal washes and monitoring leukocytosis and symptoms. Baboons vaccinated with aP were protected from severe pertussis-associated symptoms but not from colonization, did not clear the infection faster than naïve animals, and readily transmitted B. pertussis to unvaccinated contacts. Vaccination with wP induced a more rapid clearance compared with naïve and aP-vaccinated animals. By comparison, previously infected animals were not colonized upon secondary infection. Although all vaccinated and previously infected animals had robust serum antibody responses, we found key differences in T-cell immunity. Previously infected animals and wP-vaccinated animals possess strong B. pertussis-specific T helper 17 (Th17) memory and Th1 memory, whereas aP vaccination induced a Th1/Th2 response instead. The observation that aP, which induces an immune response mismatched to that induced by natural infection, fails to prevent colonization or transmission provides a plausible explanation for the resurgence of pertussis and suggests that optimal control of pertussis will require the development of improved vaccines.whooping cough | T-cell memory | animal models | adaptive immunity |

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Section: Discussionmentioning

confidence: 99%

Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model

Warfel

Zimmerman

Merkel

2013

Proc. Natl. Acad. Sci. U.S.A.

534

531

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“…Although the basis of this is still not fully clear, resurgence of pertussis is prominent in countries using acellular pertussis (aP) vaccines. It is becoming more evident that aP vaccines do not induce long lasting protection [1] and studies in animal models have suggested that aP vaccination fails to prevent nasal colonization and transmission of B. pertussis [2]. Studies in a baboon challenge model showed that immunization with an alum-formulated aP vaccine protected animals from disease, but did not prevent nasal colonization or bacterial transmission to naïve animals; nasal colonization in these animals lasted at least as long as that in unvaccinated controls [2].…”

Section: Introductionmentioning

confidence: 99%

Addition of a TLR7 agonist to an acellular pertussis vaccine enhances Th1 and Th17 responses and protective immunity in a mouse model

Misiak

Leuzzi

Allen

et al. 2017

Vaccine

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a b s t r a c tA resurgence of whooping cough (pertussis) has been observed in recent years in a number of developed countries, despite widespread vaccine coverage. Although the exact reasons of the recurrence of pertussis are not clear, there are a number of potential causes, like antigenic variation in the circulating strains of Bordetella pertussis, changes in surveillance and diagnostic tools, and potential differences in protection afforded by current acellular pertussis (aP) vaccines compared to more reactogenic whole cell (wP) vaccines, which they replaced. Studies in animal models have shown that induction of cellular as well as humoral immune responses are key to conferring effective and long lasting protection against B. pertussis. wP vaccines induce robust Th1/Th17 responses, which are associated with good protection against lung infection. In contrast, aP vaccines induce mixed Th2/Th17 responses. One research option is to modify current aP vaccines with the intention of inducing protective T cell responses, without compromising on their low reactogenicity profile. Here we found that formulation of an aP vaccine with a novel adjuvant based on a Toll-like receptor 7 agonist (TLR7a) adsorbed to aluminum hydroxide (alum) enhanced B. pertussis-specific Th1 and Th17 responses and serum IgG2a/b antibodies, which had greater functional capacity than those induced by aP formulated with alum alone. Furthermore, addition of a TLR7a enhanced the protective efficacy of the aP vaccine against B. pertussis aerosol challenge; protection was comparable to that of a wP vaccine. These findings suggest that alum-TLR7a is a promising adjuvant for clinical development of next generation pertussis vaccines.

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“…Multiple factors likely contribute to increased disease reporting, including heightened awareness, expanded surveillance, improved laboratory diagnostic testing, and allelic mismatch between circulating and vaccine reference strains (2,4,5). Waning protection conferred by acellular vaccine formulations, which replaced whole-cell preparations in the United States during the 1990s, has also led to increased disease rates among vaccinated individuals (2,(6)(7)(8).…”

mentioning

confidence: 99%

The History of Bordetella pertussis Genome Evolution Includes Structural Rearrangement

et al. 2017

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Despite high pertussis vaccine coverage, reported cases of whooping cough (pertussis) have increased over the last decade in the United States and other developed countries. Although Bordetella pertussis is well known for its limited gene sequence variation, recent advances in long-read sequencing technology have begun to reveal genomic structural heterogeneity among otherwise indistinguishable isolates, even within geographically or temporally defined epidemics. We have compared rearrangements among complete genome assemblies from 257 B. pertussis isolates to examine the potential evolution of the chromosomal structure in a pathogen with minimal gene nucleotide sequence diversity. Discrete changes in gene order were identified that differentiated genomes from vaccine reference strains and clinical isolates of various genotypes, frequently along phylogenetic boundaries defined by single nucleotide polymorphisms. The observed rearrangements were primarily large inversions centered on the replication origin or terminus and flanked by IS481, a mobile genetic element with Ͼ240 copies per genome and previously suspected to mediate rearrangements and deletions by homologous recombination. These data illustrate that structural genome evolution in B. pertussis is not limited to reduction but also includes rearrangement. Therefore, although genomes of clinical isolates are structurally diverse, specific changes in gene order are conserved, perhaps due to positive selection, providing novel information for investigating disease resurgence and molecular epidemiology.IMPORTANCE Whooping cough, primarily caused by Bordetella pertussis, has resurged in the United States even though the coverage with pertussis-containing vaccines remains high. The rise in reported cases has included increased disease rates among all vaccinated age groups, provoking questions about the pathogen's evolution. The chromosome of B. pertussis includes a large number of repetitive mobile genetic elements that obstruct genome analysis. However, these mobile elements facilitate large rearrangements that alter the order and orientation of essential protein-encoding genes, which otherwise exhibit little nucleotide sequence diversity. By comparing the complete genome assemblies from 257 isolates, we show that specific rearrangements have been conserved throughout recent evolutionary history, perhaps by eliciting changes in gene expression, which may also provide useful information for molecular epidemiology.

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Waning Protection after Fifth Dose of Acellular Pertussis Vaccine in Children

Abstract: Protection against pertussis waned during the 5 years after the fifth dose of DTaP. (Funded by Kaiser Permanente).

Cited by 487 publications

References 19 publications

Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model

Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model

Addition of a TLR7 agonist to an acellular pertussis vaccine enhances Th1 and Th17 responses and protective immunity in a mouse model

The History of Bordetella pertussis Genome Evolution Includes Structural Rearrangement

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