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 |

The interaction of the immune system with Neisseria commensals remains poorly understood. We have previously shown that phosphoethanolamine on the lipid A portion of lipooligosaccharide (LOS) plays an important role in Toll-like receptor 4 (TLR4) signaling. For pathogenic Neisseria, phosphoethanolamine is added to lipid A by the phosphoethanolamine transferase specific for lipid A, which is encoded by lptA. Here, we report that Southern hybridizations and bioinformatics analyses of genomic sequences from all eight commensal Neisseria species confirmed that lptA was absent in 15 of 17 strains examined but was present in N. lactamica. Mass spectrometry of lipid A and intact LOS revealed the lack of both pyrophosphorylation and phosphoethanolaminylation in lipid A of commensal species lacking lptA. Inflammatory signaling in human THP-1 monocytic cells was much greater with pathogenic than with commensal Neisseria strains that lacked lptA, and greater sensitivity to polymyxin B was consistent with the absence of phosphoethanolamine. Unlike the other commensals, whole bacteria of two N. lactamica commensal strains had low inflammatory potential, whereas their lipid A had high-level pyrophosphorylation and phosphoethanolaminylation and induced high-level inflammatory signaling, supporting previous studies indicating that this species uses mechanisms other than altering lipid A to support commensalism. A meningococcal lptA deletion mutant had reduced inflammatory potential, further illustrating the importance of lipid A pyrophosphorylation and phosphoethanolaminylation in the bioactivity of LOS. Overall, our results indicate that lack of pyrophosphorylation and phosphoethanolaminylation of lipid A contributes to the immune privilege of most commensal Neisseria strains by reducing the inflammatory potential of LOS.T he members of the genus Neisseria that colonize humans are classified into two pathogenic and eight commensal species. Infections due to the two pathogenic species, N. meningitidis and N. gonorrhoeae, represent a major public health problem around the world. N. meningitidis is the leading cause of epidemic meningitis, causing approximately 50,000 deaths worldwide each year (53). N. gonorrhoeae is a major cause of infections worldwide, estimated to be 60 million annually. In women, gonococcal infection can lead to pelvic inflammatory disease in 10 to 20% of those infected, causing chronic pain, infertility, and risk for ectopic pregnancy (22,42,50).Although it can be a deadly human pathogen, N. meningitidis is carried in the nasopharynx by approximately 10% of the population and only results in disease characterized by septicemia and meningitis at low frequencies (65). Asymptomatic carriage of N. meningitidis, which is infrequent in infancy and peaks in early adulthood, is the mechanism by which the reservoir of meningococci is maintained within the population. Similarly, asymptomatic gonococcal infection of women plays an important role in maintaining transmission of the organism (16).The eight commensal Nei...

Our results demonstrate that neonatal vaccination and maternal vaccination confer protection in the baboon model and support further study of these strategies for protection of newborns from pertussis.

Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis. Pertussis rates in the United States have escalated since the 1990s and reached a 50-year high of 48,000 cases in 2012. While this pertussis resurgence is not completely understood, we previously showed that the current acellular pertussis vaccines do not prevent colonization or transmission following challenge. In contrast, a whole-cell pertussis vaccine accelerated the rate of clearance compared to rates in unvaccinated animals and animals treated with the acellular vaccine. In order to understand if these results are generalizable, we used our baboon model to compare immunity from whole-cell vaccines from three different manufacturers that are approved outside the United States. We found that, compared to clearance rates with no vaccine and with an acellular pertussis vaccine, immunization with any of the three whole-cell vaccines significantly accelerated the clearance of B. pertussis following challenge. Whole-cell vaccination also significantly reduced the total nasopharyngeal B. pertussis burden, suggesting that these vaccines reduce the opportunity for pertussis transmission. Meanwhile, there was no difference in either the duration or in B. pertussis burden between unvaccinated and acellular-pertussis-vaccinated animals, while previously infected animals were not colonized following reinfection. We also determined that transcription of the gene encoding interleukin-17 (IL-17) was increased in wholecell-vaccinated and previously infected animals but not in acellular-pertussis-vaccinated animals following challenge. Together with our previous findings, these data are consistent with a role for Th17 responses in the clearance of B. pertussis infection. Whooping cough is a highly contagious, acute respiratory illness caused by the bacterial pathogen Bordetella pertussis (1). In the prevaccine era, pertussis was rampant in the United States with annual reported cases ranging from 150,000 to 250,000 per year and with fatality rates approaching 10% (2). The introduction of combination diphtheria, tetanus, and whole-cell pertussis (DTwP) vaccines in the 1940s and a gradual increase in vaccine coverage led to a dramatic decrease in pertussis incidence with a nadir of 1,000 cases reported in 1976. Due to concerns over the reactogenicity of the whole-cell pertussis vaccine and the prospects of diminishing acceptance among parents, combination diphtheria, tetanus, and acellular pertussis (DTaP) vaccines were introduced in the United States in 1991 and replaced whole-cell vaccines for all pertussis vaccinations in 1997. Currently acellular vaccines are the only pertussis vaccines licensed in the United States and much of the developed world (3). However, despite 95% vaccine coverage in infants, the annual number of reported pertussis cases has been rising over the last 20 to 30 years in the United States (4, 5). The rate of pertussis resurgence increased dramatically following the introduction of acellular vac...