Protective effect of PCV vaccine against experimental pneumococcal challenge in adults is primarily mediated by controlling colonisation density

German, Esther L.; Solórzano, Carla; Sunny, Syba; Dunne, F.; Gritzfeld, Jenna F.; Mitsi, Elena; Nikolaou, Elissavet; Hyder-Wright, Angela; Collins, Andrea; Gordon, Stephen B.; Ferreira, Daniela M.

doi:10.1016/j.vaccine.2019.05.080

Cited by 23 publications

(19 citation statements)

References 19 publications

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“…Following exposure, 41 volunteers remained culture-negative (41/63, 65.1%) and 22 became culture-positive (see Table S1 in the supplemental material). Colonization status was confirmed by S. pneumoniae 6A/B capsule-specific and lytA -specific quantitative PCR (qPCR) in nasal wash to ensure that we did not miss low-density colonizers ( 18 ). Only one culture-negative volunteer showed a low positive signal (threshold cycle [ C T ] = 37) at day 6 post S. pneumoniae exposure.…”

Section: Resultsmentioning

confidence: 99%

Experimental Human Challenge Defines Distinct Pneumococcal Kinetic Profiles and Mucosal Responses between Colonized and Non-Colonized Adults

Nikolaou

Jochems

Mitsi

et al. 2021

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Colonization of the upper respiratory tract with Streptococcus pneumoniae is the precursor of pneumococcal pneumonia and invasive disease. Following exposure, however, it is unclear which human immune mechanisms determine whether a pathogen will colonize. We used a human challenge model to investigate host-pathogen interactions in the first hours and days following intranasal exposure to Streptococcus pneumoniae. Using a novel home sampling method, we measured early immune responses and bacterial density dynamics in the nose and saliva after volunteers were experimentally exposed to pneumococcus. Here, we show that nasal colonization can take up to 24 h to become established. Also, the following two distinct bacterial clearance profiles were associated with protection: nasal clearers with immediate clearance of bacteria in the nose by the activity of pre-existent mucosal neutrophils and saliva clearers with detectable pneumococcus in saliva at 1 h post challenge and delayed clearance mediated by an inflammatory response and increased neutrophil activity 24 h post bacterial encounter. This study describes, for the first time, how colonization with a bacterium is established in humans, signifying that the correlates of protection against pneumococcal colonization, which can be used to inform design and testing of novel vaccine candidates, could be valid for subsets of protected individuals. IMPORTANCE Occurrence of lower respiratory tract infections requires prior colonization of the upper respiratory tract with a pathogen. Most bacterial infection and colonization studies have been performed in murine and in vitro models due to the current invasive sampling methodology of the upper respiratory tract, both of which poorly reflect the complexity of host-pathogen interactions in the human nose. Self-collecting saliva and nasal lining fluid at home is a fast, low-cost, noninvasive, high-frequency sampling platform for continuous monitoring of bacterial encounter at defined time points relative to exposure. Our study demonstrates for the first time that, in humans, there are distinct profiles of pneumococcal colonization kinetics, distinguished by speed of appearance in saliva, local phagocytic function, and acute mucosal inflammatory responses, which may either recruit or activate neutrophils. These data are important for the design and testing of novel vaccine candidates.

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Section: Resultsmentioning

confidence: 99%

Experimental Human Challenge Defines Distinct Pneumococcal Kinetic Profiles and Mucosal Responses between Colonized and Non-Colonized Adults

Nikolaou

Jochems

Mitsi

et al. 2021

mBio

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“…[34] In an experimental human pneumococcal challenge model, adults who received PCV13 had lower pneumococcal density compared with those who received a control vaccine. [37] To date, there is not consistent evidence of an effect of PCV on pneumococcal density in children. Variations in density observed in cross-sectional studies with carriage assessed during different years may be temporal and/or related to as number of unmeasured factors.…”

Section: Discussionmentioning

confidence: 99%

Factors associated with pneumococcal carriage and density in infants and young children in Laos PDR

et al. 2019

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Nasopharyngeal carriage of Streptococcus pneumoniae (the pneumococcus) is a precursor to pneumococcal disease. Several host and environmental factors have been associated with pneumococcal carriage, however few studies have examined the relationship between host factors and pneumococcal carriage density. We sought to identify risk factors for pneumococcal carriage and density using data from cross-sectional pneumococcal carriage surveys conducted in the Lao People's Democratic Republic before and after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). Nasopharyngeal swabs were collected infants from aged 5–8 weeks old (n = 999) and children aged 12–23 months (n = 1,010), pneumococci detected by quantitative PCR, and a risk factor questionnaire completed. Logistic and linear regression models were used to evaluate associations between participant characteristics and pneumococcal carriage and density. In infants aged 5–8 weeks, living in a household with two or more children under the age of five years (aOR 1.97; 95% CI 1.39–2.79) and low family income (aOR 1.64; 95% CI 0.99–2.72) were positively associated with pneumococcal carriage. For children aged 12–23 months, upper respiratory tract infection (URTI) symptoms (aOR 2.64; 95% CI 1.97–3.53), two or more children under five in the household (aOR 2.40; 95% CI 1.80–3.20), and rural residence (aOR 1.84, 95% CI 1.35–2.50) were positively associated with pneumococcal carriage. PCV13 vaccination was negatively associated with carriage of PCV13 serotypes (aOR 0.60; 95% CI 0.44–0.83). URTI symptoms (p < 0.001), current breastfeeding (p = 0.005), rural residence (p = 0.012), and delivery by Caesarean section (p = 0.035) were associated with higher mean pneumococcal density in pneumococcal carriers (both age groups combined). This study provides new data on pneumococcal carriage and density in a high disease burden setting in southeast Asia.

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“…Those that do, have heterogeneous findings. A double-blind, randomized controlled trial of PCV13 and Hepatitis A vaccine (control arm) in adults, using the Experimental Human Pneumococcal Challenge model, found that pneumococcal density in the PCV13 arm was significantly lower compared with the control arm (P<0.0001) [60]. In a cluster-randomized trial of PCV7 and Meningococcal C vaccine (control arm) in rural Gambia, density of PCV7 pneumococcal carriage was lower in PCV7 villages compared with control arm villages [61].…”

Section: Plos Onementioning

confidence: 99%

Factors associated with pneumococcal carriage and density in children and adults in Fiji, using four cross-sectional surveys

et al. 2020

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This study describes predictors of pneumococcal nasopharyngeal carriage and density in Fiji. We used data from four annual (2012-2015) cross-sectional surveys, pre-and postintroduction of ten-valent pneumococcal conjugate vaccine (PCV10) in October 2012. Infants (5-8 weeks), toddlers (12-23 months), children (2-6 years), and their caregivers participated. Pneumococci were detected and quantified using lytA qPCR, with molecular serotyping by microarray. Logistic and quantile regression were used to determine predictors of pneumococcal carriage and density, respectively. There were 8,109 participants. Pneumococcal carriage was negatively associated with years post-PCV10 introduction (global P<0.001), and positively associated with indigenous iTaukei ethnicity (aOR 2.74 [95% CI 2.17-3.45] P<0.001); young age (infant, toddler, and child compared with caregiver participant groups) (global P<0.001); urban residence (aOR 1.45 [95% CI 1.30-2.57] P<0.001); living with �2 children <5 years of age (aOR 1.42 [95% CI 1.27-1.59] P<0.001); low family income (aOR 1.44 [95% CI 1.28-1.62] P<0.001); and upper respiratory tract infection (URTI) symptoms (aOR 1.77 [95% CI 1.57-2.01] P<0.001). Predictors were similar for PCV10 and non-PCV10 carriage, except PCV10 carriage was negatively associated with PCV10 vaccination (0.58 [95% CI 0.41-0.82] P = 0.002) and positively associated with exposure to household cigarette smoke (aOR 1.21 [95% CI 1.02-1.43] P = 0.031), while there was no association between years post-PCV10 introduction and non-PCV10 carriage. Pneumococcal density was positively associated with URTI symptoms (adjusted median difference 0.28 [95% CI 0.16, 0.40] P<0.001) and toddler and child, compared with caregiver, participant groups (global P = 0.008). Predictors were similar for PCV10 and non-PCV10 density, except infant, toddler, and child participant groups were not associated with PCV10 density. PCV10 introduction was associated with reduced the odds of overall and PCV10 pneumococcal carriage in Fiji. However, after adjustment iTaukei ethnicity was positively

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Protective effect of PCV vaccine against experimental pneumococcal challenge in adults is primarily mediated by controlling colonisation density

Cited by 23 publications

References 19 publications

Experimental Human Challenge Defines Distinct Pneumococcal Kinetic Profiles and Mucosal Responses between Colonized and Non-Colonized Adults

Experimental Human Challenge Defines Distinct Pneumococcal Kinetic Profiles and Mucosal Responses between Colonized and Non-Colonized Adults

Factors associated with pneumococcal carriage and density in infants and young children in Laos PDR

Factors associated with pneumococcal carriage and density in children and adults in Fiji, using four cross-sectional surveys

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