Pneumococcal conjugate vaccine induced IgG and nasopharyngeal carriage of pneumococci: Hyporesponsiveness and immune correlates of protection for carriage.

BACKGROUND: Prior studies have demonstrated hyporesponsiveness to pneumococcal conjugate vaccines (PCVs) when administered in the presence of homologous carriage. This may be substantially more important in Africa where carriage prevalence is high. Deriving a correlate of protection (CoP) for carriage is important in guiding the future use of extended PCVs as population control of pneumococcal disease by vaccination is now focused principally on its indirect effect. We therefore explored the complex relationship between existing carriage and vaccine responsiveness, and between serum IgG levels and risk of acquisition. METHODS: We undertook secondary analyses of data from two previously published clinical trials of the safety and immunogenicity of PCV in Kenya. We compared responses to vaccination between serotype-specific carriers and non-carriers at vaccination. We assessed the risk of carriage acquisition in relation to PCV-induced serum IgG levels using either a step- or continuous-risk function. RESULTS: For newborns, the immune response among carriers was 51-82% lower than that among non-carriers, depending on serotype. Among toddlers, for serotypes 6B, 14 and 19F the post-vaccination response among carriers was lower by between 29 and 70%. The estimated CoP against acquisition ranged from 0.26 to 1.93?g/mL across serotypes, however, these thresholds could not be distinguished statistically from a model with constant probability of carriage independent of assay value. CONCLUSION: We have confirmed hyporesponsiveness in an equatorial African setting in both infants and toddlers. Population responses to vaccination are likely to improve with time as carriage prevalence of vaccine serotypes is reduced. We have not found clear correlates of protection against carriage acquisition among toddlers in this population. Assessing the potential of new vaccines through the use of CoP against carriage is still difficult as there are no clear-cut serotype specific correlates

Airway Epithelial Innate Immunity

Besides providing an essential protective barrier, airway epithelial cells directly sense pathogens and respond defensively. This is a frontline component of the innate immune system with specificity for different pathogen classes. It occurs in the context of numerous interactions with leukocytes, but here we focus on intrinsic epithelial mechanisms. Type 1 immune responses are directed primarily at intracellular pathogens, particularly viruses. Prominent stimuli include microbial nucleic acids and interferons released from neighboring epithelial cells. Epithelial responses revolve around changes in the expression of interferon-sensitive genes (ISGs) that interfere with viral replication, as well as the further induction of interferons that signal in autocrine and paracrine manners. Type 2 immune responses are directed primarily at helminths and fungi. Prominent pathogen stimuli include proteases and chitin, and important responses include mucin hypersecretion and chitinase release. Type 3 immune responses are directed primarily at extracellular microbial pathogens, including bacteria and fungi, as well as viruses during their extracellular phase of infection. Prominent microbial stimuli include bacterial wall components, such as lipopeptides and endotoxin, as well as microbial nucleic acids. Key responses are the release of reactive oxygen species (ROS) and antimicrobial peptides (AMPs). For all three types of response, paracrine signaling to neighboring epithelial cells induces resistance to infection over a wide field. Often, the epithelial effector molecules themselves also have signaling properties, in addition to the release of inflammatory cytokines that boost local innate immunity. Together, these epithelial mechanisms provide a powerful first line of pathogen defense, recruit leukocytes, and instruct adaptive immune responses

The Potential for Reducing the Number of Pneumococcal Conjugate Vaccine Doses While Sustaining Herd Immunity in High-Income Countries.

Stefan Flasche and colleagues consider whether the number of PCV doses in the infant schedule could be reduced without compromising its public health benefit in high-income settings

Effect of Haemophilus influenzae type b vaccination without a booster dose on invasive H influenzae type b disease, nasopharyngeal carriage, and population immunity in Kilifi, Kenya: a 15-year regional surveillance study

Background Haemophilus infl uenzae type b (Hib) conjugate vaccine, delivered as a three-dose series without a booster, was introduced into the childhood vaccination programme in Kenya in 2001. The duration of protection and need for a booster dose are unknown. We aimed to assess vaccine eff ectiveness, the impact of the vaccine on nasopharyngeal carriage, and population immunity after introduction of conjugate Hib vaccine in infancy without a booster dose in Kenya. Methods This study took place in the Kilifi Health and Demographic Surveillance System (KHDSS), an area of Kenya that has been monitored for vital events and migration every 4 months since 2000. We analysed sterile site cultures for H infl uenzae type b from children (aged ≤12 years) admitted to the Kilifi County Hospital (KCH) from Jan 1, 2000, through to Dec 31, 2014. We determined the prevalence of nasopharyngeal carriage by undertaking cross-sectional surveys in random samples of KHDSS residents (of all ages) once every year from 2009 to 2012, and measured Hib antibody concentrations in fi ve cross-sectional samples of children (aged ≤12 years) within the KHDSS (in 1998, 2000, 2004–05, 2007, and 2009). We calculated incidence rate ratios between the prevaccine era (2000–01) and the routineuse era (2004–14) and defi ned vaccine eff ectiveness as 1 minus the incidence rate ratio, expressed as a percentage. Findings 40 482 children younger than 13 years resident in KHDSS were admitted to KCH between 2000 and 2014, 38 206 (94%) of whom had their blood cultured. The incidence of invasive H infl uenzae type b disease in children younger than 5 years declined from 62·6 (95% CI 46·0–83·3) per 100 000 in 2000–01 to 4·5 (2·5–7·5) per 100 000 in 2004–14, giving a vaccine eff ectiveness of 93% (95% CI 87–96). In the fi nal 5 years of observation (2010–14), only one case of invasive H infl uenzae type b disease was detected in a child younger than 5 years. Nasopharyngeal H infl uenzae type b carriage was detected in one (0·2%) of 623 children younger than 5 years between 2009 and 2012. In the 2009 serosurvey, 92 (79%; 95% CI 70–86) of 117 children aged 4–35 months had long-term protective antibody concentrations. Interpretation In this region of Kenya, use of a three-dose primary series of Hib vaccine without a booster dose has resulted in a signifi cant and sustained reduction in invasive H infl uenzae type b disease. The prevalence of nasopharyngeal carriage is low and the profi le of Hib antibodies suggests that protection wanes only after the age at greatest risk of disease. Although continued surveillance is important to determine whether eff ective control persists, these fi ndings suggest that a booster dose is not currently required in Kenya

Epithelial immunomodulation by aerosolized Toll-like receptor agonists prevents allergic inflammation in airway mucosa in mice

Allergic asthma is a chronic inflammatory respiratory disease associated with eosinophilic infiltration, increased mucus production, airway hyperresponsiveness, and airway remodeling. Epidemiologic data reveal that the prevalence of allergic sensitization and associated diseases has increased in the twentieth century. This has been hypothesized to be partly due to reduced contact with microbial organisms (the hygiene hypothesis) in industrialized society. Airway epithelial cells, once considered a static physical barrier between the body and the external world, are now widely recognized as immunologically active cells that can initiate, maintain, and restrain inflammatory responses, such as those that mediate allergic disease. Airway epithelial cells can sense allergens via expression of myriad Toll-like receptors (TLRs) and other pattern-recognition receptors. We sought to determine whether the innate immune response stimulated by a combination of Pam2CSK4 (“Pam2”, TLR2/6 ligand) and a class C oligodeoxynucleotide ODN362 (“ODN”, TLR9 ligand), when delivered together by aerosol (“Pam2ODN”), can modulate the allergic immune response to allergens. Treatment with Pam2ODN 7 days before sensitization to House Dust Mite (HDM) extract resulted in a strong reduction in eosinophilic and lymphocytic inflammation. This Pam2ODN immunomodulatory effect was also seen using Ovalbumin (OVA) and A. oryzae (Ao) mouse models. The immunomodulatory effect was observed as much as 30 days before sensitization to HDM, but ineffective just 2 days after sensitization, suggesting that Pam2ODN immunomodulation lowers the allergic responsiveness of the lung, and reduces the likelihood of inappropriate sensitization to aeroallergens. Furthermore, Pam2 and ODN cooperated synergistically suggesting that this treatment is superior to any single agonist in the setting of allergen immunotherapy

Pneumococcal carriage following PCV13 delivered as one primary and one booster dose (1 + 1) compared to two primary doses and a booster (2 + 1) in UK infants

In January 2020 the UK changed from a 2 + 1 schedule for 13-valent pneumococcal conjugate vaccine (PCV13) to a 1 + 1 schedule (doses at 3 and 12 months) based on a randomized immunogenicity trial comparing the two schedules. Carriage prevalence measured at the time of booster and 6 months later in 191 of the 213 study infants was 57 % (109/191) and 60 % (114/190) respectively. There were eight episodes of vaccine-type (VT) or vaccine-related 6C carriage in the 2 + 1 and six in the 1 + 1 group; ≥4-fold rises in serotype-specific IgG in 71 children with paired post-booster and follow up blood samples at 21–33 months of age were found in 20 % (7/35) of the 2 + 1 and 15 % (6/41) of the 1 + 1 group. VTs identified in carriage and inferred from serology were similar comprising 3, 19A and 19F. Dropping a priming dose from the 2 + 1 PCV 13 schedule did not increase VT carriage in the study cohort. Ongoing population level carriage studies will be important to confirm this

Population immunity to pneumococcal serotypes in Kilifi, Kenya, before and 6 years after the introduction of PCV10 with a catch-up campaign: an observational study of cross-sectional serosurveys

BACKGROUND: In Kilifi (Kenya), a pneumococcal conjugate vaccine (PCV10) was introduced in 2011 in infants (aged <1 year, 3 + 0 schedule) with a catch-up campaign in children aged 1-4 years. We aimed to measure the effect of PCV10 on population immunity. METHODS: In this observational study, repeated cross-sectional serosurveys were conducted in independent random samples of 500 children younger than 15 years every 2 years between 2009 and 2017. During these surveys, blood samples were collected by venesection. Concentrations of anti-capsular IgGs against vaccine serotypes (VTs) 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, and against serotypes 6A and 19A, were assayed by ELISA. We plotted the geometric mean concentrations (GMCs) by birth year to visualise age-specific antibody profiles. In infants, IgG concentrations of 0·35 μg/mL or higher were considered protective. FINDINGS: Of 3673 volunteers approached, 2152 submitted samples for analysis across the five surveys. Vaccine introduction resulted in an increase in the proportion of young children with protective IgG concentrations, compared with before vaccine introduction (from 0-33% of infants with VT-specific levels over the correlate of protection in 2009, to 60-94% of infants in 2011). However, among those vaccinated in infancy, GMCs of all ten VTs had waned rapidly by the age of 1, but rose again later in childhood. GMCs among children aged 10-14 years were consistently high over time (eg, the range of GMCs across survey rounds were between 0·45 μg/mL and 1·00 μg/mL for VT 23F and between 2·00 μg/mL and 3·11 μg/mL for VT 19F). INTERPRETATION: PCV10 in a 3 + 0 schedule elicited protective IgG levels during infancy, when disease risk is high. The high antibody levels in children aged 10-14 years might indicate continued exposure to vaccine serotypes due to residual carriage or to memory responses to cross-reactive antigens. Despite rapid waning of IgG after vaccination, disease incidence among young children in this setting remains low, suggesting that lower thresholds of antibody, or other markers of immunity (eg, memory B cells), may be needed to assess population protection among children who have aged past infancy. FUNDING: Gavi, the Vaccine Alliance; Wellcome Trust

Population immunity to pneumococcal serotypes in Kilifi, Kenya, before and 6 years after the introduction of PCV10 with a catch-up campaign: an observational study of cross-sectional serosurveys

BACKGROUND: In Kilifi (Kenya), a pneumococcal conjugate vaccine (PCV10) was introduced in 2011 in infants (aged <1 year, 3 + 0 schedule) with a catch-up campaign in children aged 1-4 years. We aimed to measure the effect of PCV10 on population immunity. METHODS: In this observational study, repeated cross-sectional serosurveys were conducted in independent random samples of 500 children younger than 15 years every 2 years between 2009 and 2017. During these surveys, blood samples were collected by venesection. Concentrations of anti-capsular IgGs against vaccine serotypes (VTs) 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, and against serotypes 6A and 19A, were assayed by ELISA. We plotted the geometric mean concentrations (GMCs) by birth year to visualise age-specific antibody profiles. In infants, IgG concentrations of 0·35 μg/mL or higher were considered protective. FINDINGS: Of 3673 volunteers approached, 2152 submitted samples for analysis across the five surveys. Vaccine introduction resulted in an increase in the proportion of young children with protective IgG concentrations, compared with before vaccine introduction (from 0-33% of infants with VT-specific levels over the correlate of protection in 2009, to 60-94% of infants in 2011). However, among those vaccinated in infancy, GMCs of all ten VTs had waned rapidly by the age of 1, but rose again later in childhood. GMCs among children aged 10-14 years were consistently high over time (eg, the range of GMCs across survey rounds were between 0·45 μg/mL and 1·00 μg/mL for VT 23F and between 2·00 μg/mL and 3·11 μg/mL for VT 19F). INTERPRETATION: PCV10 in a 3 + 0 schedule elicited protective IgG levels during infancy, when disease risk is high. The high antibody levels in children aged 10-14 years might indicate continued exposure to vaccine serotypes due to residual carriage or to memory responses to cross-reactive antigens. Despite rapid waning of IgG after vaccination, disease incidence among young children in this setting remains low, suggesting that lower thresholds of antibody, or other markers of immunity (eg, memory B cells), may be needed to assess population protection among children who have aged past infancy. FUNDING: Gavi, the Vaccine Alliance; Wellcome Trust

Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial

BACKGROUND: The development of vaccines to control the COVID-19 pandemic progression is a worldwide priority. CoronaVac® is an inactivated SARS-CoV-2 vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. METHODS: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac® separated by two (0-14 schedule) or four weeks (0-28 schedule). 2,302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured. RESULTS: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern between schedules. Stimulation of PBMCs with MPs induced the secretion of IFN-g and the expression of activation induced markers for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-g secretion. CONCLUSIONS: Immunization with CoronaVac® in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule. FUNDING: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. CLINICAL TRIAL NUMBER: NCT04651790