Safety and immunogenicity of a new formulation of a pentavalent DTwP-HepB-Hib vaccine in healthy Indian infants-A randomized study.

BACKGROUND: Pentavalent vaccines (DTP-HepB-Hib) have been introduced in many countries in their routine public immunization programmes to protect against diphtheria (D), tetanus (T), pertussis (P), hepatitis B (Hep B) and Hemophilus influenzae type b (Hib) diseases. This study compared the safety and immunogenicity of a new formulation of a whole-cell Bordetella pertussis (wP) based pentavalent vaccine (DTwP-HepB-Hib). The new formulation was developed using well-characterized hepatitis B and pertussis whole cell vaccine components. METHODS: This was a phase III, observer-blind, randomized, non-inferiority, multi-center study conducted in India among 460 infants who were followed up for safety and immunogenicity for 28 days after administration of three doses of either investigational or licensed comparator formulations at 6-8, 10-12 and 14-16 weeks of age. RESULTS: The investigational formulation of DTwP-HepB-Hib vaccine was non-inferior to the licensed formulation in terms of hepatitis B seroprotection rate (% of subjects with HepB antibodies ≥10mIU/mL were 99.1% versus 99.0%, respectively, corresponding to a difference of 0.1% (95% CI, -2.47 to 2.68)) and pertussis immune responses (adjusted geometric mean concentrations of antibodies for anti-PT were 76.7 EU/mL versus 63.3 EU/mL, with a ratio of aGMTs of 1.21 (95% CI, 0.89-1.64), and for anti-FIM were 1079 EU/mL versus 1129 EU/mL, with a ratio of aGMTs of 0.95 (95% CI, 0.73-1.24), respectively). The immune responses to other valences (D, T, and Hib) in the two formulations were also similar. The safety profile of both formulations was found to be similar and were well tolerated. CONCLUSIONS: The investigational DTwP-HepB-Hib vaccine formulation was immunogenic and well-tolerated when administered as three dose primary series in infants. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry India number: CTRI/2018/12/016692.

Immunogenicity and Safety of a Hexavalent DTwP-IPV-HB-PRP~T Vaccine Versus Separate DTwP-HB-PRP~T, bOPV, and IPV Vaccines Administered at 2, 4, 6 Months of Age Concomitantly With Rotavirus and Pneumococcal Conjugate Vaccines in Healthy Infants in Thailand.

BACKGROUND: This study investigated the immunogenicity and safety of a fully liquid, hexavalent, diphtheria (D)-tetanus (T)-whole-cell pertussis (wP)-inactivated poliovirus (IPV)-hepatitis B (HB)- Haemophilus influenzae b (PRP-T) vaccine compared to licensed DTwP-HB-PRP~T, IPV, and bivalent oral poliovirus (bOPV) vaccines following co-administration with other pediatric vaccines [pneumococcal conjugate vaccine (PCV13) and rotavirus vaccine]. METHODS: Phase III, randomized, open-label study in Thailand. Healthy infants received DTwP-IPV-HB-PRP~T at 2, 4 and 6 months of age (N = 228), or DTwP-HB-PRP~T and bOPV (2, 4 and 6 months of age) and IPV (4 months of age) (N = 231). All participants received PCV13 (2, 4 and 6 months of age) and rotavirus vaccine (2 and 4 months of age). Immunogenicity for all antigens was assessed using validated assays, and noninferiority post-third dose was evaluated for anti-D, anti-T, anti-pertussis [anti-pertussis toxin (anti-PT) and anti-fimbriae 2/3 (anti-FIM)], anti-polio 1, 2, 3, anti-HB, and anti-PRP~T. Safety was assessed using parental reports. RESULTS: Noninferiority was demonstrated for each antigen, and overall noninferiority of DTwP-IPV-HB-PRP~T versus DTwP-HB-PRP~T+bOPV+IPV was concluded. Similarity in each group was observed for the GMC ratio for antirotavirus antibodies (20.9 and 17.3, respectively) and anti-PCV13 antibodies (range: 8.46-32.6 and 7.53-33.1, respectively). Two serious adverse events were related to DTwP-IPV-HB-PRP~T (febrile convulsion and acute febrile illness) and 1 was related to DTwP-HB-PRP~T+bOPV+IPV (febrile seizure), but overall there were no safety concerns with similar rates of participants experiencing solicited (99.1% and 98.3%) and unsolicited (19.3% and 19.5%) adverse events in each group. CONCLUSIONS: This study confirmed the suitability of DTwP-IPV-HB-PRP~T primary series vaccination in combination with rotavirus and PCV13 vaccines.

Immunogenicity of a new enhanced tetanus-reduced dose diphtheria-acellular pertussis (Tdap) vaccine against Bordetella pertussis in a murine model.

BACKGROUND: The necessity of the tetanus-reduced dose diphtheria-acellular pertussis (Tdap) vaccine in adolescence and adults has been emphasized since the resurgence of small-scale pertussis in Korea and worldwide due to the waning effect of the vaccine and variant pathogenic stains in the late 1990s. GreenCross Pharma (GC Pharma), a Korean company, developed the Tdap vaccine GC3111 in 2010. Recently, they enhanced the vaccine, GC3111, produced previously in 2010 to reinforce the antibody response against filamentous hemagglutinin (FHA). In this study, immunogenicity and efficacy of the enhanced Tdap vaccine compared and evaluated with two Tdap vaccines, GC3111 vaccine produced in 2010 previously and commercially available Tdap vaccine in a murine model. METHODS: Two tests groups and positive control group of Balb/c mice were primed with two doses of the diphtheria-tetanus-acellular pertussis (DTaP) vaccine followed by a single booster Tdap vaccine at 9 week using the commercially available Tdap vaccine or 2 Tdap vaccines from GC Pharma (GC3111, enhanced GC3111). Humoral response was assessed 1 week before and 2 and 4 weeks after Tdap booster vaccination. The enhanced GC3111 generated similar humoral response compare to the commercial vaccine for filamentous hemagglutinin (FHA). The interferon gamma (IFN-γ) (Th1), interleukin 5 (IL-5) (Th2) and interleukin 17 (IL-17) (Th17) cytokines were assessed 4 weeks after booster vaccination by stimulation with three simulators: heat inactivated Bordetella pertussis (hBp), vaccine antigens, and hBp mixed with antigens (hBp + antigen). A bacterial challenge test was performed 4 weeks after booster vaccination. RESULTS: Regarding cell-mediated immunity, cytokine secretion differed among the three simulators. However, no difference was found between two test groups and positive control group. All the vaccinated groups indicated a Th1 or Th1/Th2 response. On Day 5 post-bacterial challenge, B. pertussis colonies were absent in the lungs in two test groups and positive control group. CONCLUSIONS: Our results confirmed the immunogenicity of GC Pharma's Tdap vaccine; enhanced GC3111 was equivalent to the presently used commercial vaccine in terms of humoral response as well as cell-mediated cytokine expression.

Effectiveness of experimental and commercial pertussis vaccines in the elimination of Bordetella pertussis isolates with different genetic profiles in murine model.

The aim of this study was to compare the elimination of Bordetella pertussis clinical isolates, representing different genotypes in relation to alleles encoding virulence factors (MLST-multi-locus antigen sequence typing), MLVA type (multi-locus variable-number tandem repeat analysis) and PFGE group (pulsed-field gel electrophoresis) from the lungs of naive mice or mice were immunised with the commercial whole-cell pertussis vaccine, the acellular pertussis vaccine and the experimental whole-cell pertussis vaccine. Molecular data indicate that the resurgence of pertussis in populations with high vaccine coverage is associated with genomic adaptation of B. pertussis, to vaccine selection pressure. Pertactin-negative B. pertussis isolates were suspected to contribute to the reduced vaccine effectiveness. It was shown that one of the isolates used is PRN deficient. The mice were intranasally challenged with bacterial suspension containing approximately 5 × 10 7 CFU/ml B. pertussis. The immunogenicity of the tested vaccines against PT (pertussis toxin), PRN (pertactin), FHA (filamentous haemagglutinin) and FIM (fimbriae types 2 and 3) was examined. The commercial whole-cell and acellular pertussis vaccines induced an immunity effective at eliminating the genetically different B. pertussis isolates from the lungs. However, the elimination of the PRN-deficient isolate from the lungs of mice vaccinated with commercial vaccines was delayed as compared to the PRN ( +) isolate, suggesting phenotypic differences with the circulating isolates and vaccine strains. The most effective vaccine was the experimental vaccine with the composition identical to that of the strains used for infection.

Repurposing of the childhood vaccines: could we train the immune system against the SARS-CoV-2.

INTRODUCTION: The COVID-19 pandemic is a globalized health concern caused by a beta-coronavirus named Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Since December 2019, when this outbreak flared in Wuhan, China, COVID-19 cases have been continuously rising all over the world. Due to the emergence of SARS-CoV-2 mutants, subsequent waves are flowing in a faster manner as compared to the primary wave, which is more contagious and causing higher mortality. Recently, India has emerged as the new epicenter of the second wave by mutants of SARS-CoV-2. After almost eighteen months of this outbreak, some COVID-19 dedicated therapeutics and vaccines are available, and a few are under trial, but the situation is still uncontrolled. AREA COVERED: This perspective article covers the repurposing of childhood vaccines like Bacille Calmette-Guerin (BCG), Measles, Mumps, Rubella (MMR), and Oral Polio Vaccine (OPV), which are live attenuated vaccines and have been shown the protective effect through 'trained immunity and 'crossreactivity.' EXPERT OPINION: This perspective article has suggested that combinatorial use of these childhood vaccines might exert a better protective effect along with the available COVID-19 therapeutic and vaccines which could be considered as a preventive option against SARS-CoV-2 infection as well as its subsequent waves.

Response to Vaccination in Infants Exposed to Antitumor Necrosis Factor Alpha In Utero.

In this retrospective cohort study, the response to routinely administered Haemophilus influenzae type B vaccine, pneumococcal and pertussis vaccinations in 27 children exposed to antitumor necrosis factor alpha (anti-TNFα) during pregnancy was measured. The overall vaccination response seems comparable for children exposed to anti-TNFα and healthy infants. After primary vaccination series, inadequate response was present in some patients and might be related to exposure to anti-TNFα.

Highly Sensitive Flow Cytometry Allows Monitoring of Changes in Circulating Immune Cells in Blood After Tdap Booster Vaccination.

Antigen-specific serum immunoglobulin (Ag-specific Ig) levels are broadly used as correlates of protection. However, in several disease and vaccination models these fail to predict immunity. In these models, in-depth knowledge of cellular processes associated with protective versus poor responses may bring added value. We applied high-throughput multicolor flow cytometry to track over-time changes in circulating immune cells in 10 individuals following pertussis booster vaccination (Tdap, Boostrix®, GlaxoSmithKline). Next, we applied correlation network analysis to extensively investigate how changes in individual cell populations correlate with each other and with Ag-specific Ig levels. We further determined the most informative cell subsets and analysis time points for future studies. Expansion and maturation of total IgG1 plasma cells, which peaked at day 7 post-vaccination, was the most prominent cellular change. Although these cells preceded the increase in Ag-specific serum Ig levels, they did not correlate with the increase of Ig levels. In contrast, strong correlation was observed between Ag-specific IgGs and maximum expansion of total IgG1 and IgA1 memory B cells at days 7 to 28. Changes in circulating T cells were limited, implying the need for a more sensitive approach. Early changes in innate immune cells, i.e. expansion of neutrophils, and expansion and maturation of monocytes up to day 5, most likely reflected their responses to local damage and adjuvant. Here we show that simultaneous monitoring of multiple circulating immune subsets in blood by flow cytometry is feasible. B cells seem to be the best candidates for vaccine monitoring.

Circulation of pertussis and poor protection against diphtheria among middle-aged adults in 18 European countries.

Reported incidence of pertussis in the European Union (EU) and the European Economic Area (EEA) varies and may not reflect the real situation, while vaccine-induced protection against diphtheria and tetanus seems sufficient. We aimed to determine the seroprevalence of DTP antibodies in EU/EEA countries within the age groups of 40-49 and 50-59 years. Eighteen countries collected around 500 samples between 2015 and 2018 (N = 10,302) which were analysed for IgG-DTP specific antibodies. The proportion of sera with pertussis toxin antibody levels ≥100 IU/mL, indicative of recent exposure to pertussis was comparable for 13/18 countries, ranging between 2.7-5.8%. For diphtheria the proportion of sera lacking the protective level (<0.1 IU/mL) varied between 22.8-82.0%. For tetanus the protection was sufficient. Here, we report that the seroprevalence of pertussis in these age groups indicates circulation of B. pertussis across EU/EEA while the lack of vaccine-induced seroprotection against diphtheria is of concern and deserves further attention.

Effect of Haemophilus influenzae Type b Vaccination on Nasopharyngeal Carriage Rate in Children, Tehran, 2019.

BACKGROUND: Haemophilus influenzae (H. influenzae) strains, which commonly reside as commensals within the human pharynx and can remain as an asymptomatic carrier, but become invasive leading to pneumonia, septic arthritis, or meningitis. The Pentavac (pentavalent vaccine, manufactured by India, SII (DTwP-HepB-Hib)) was introduced to the Iranian National Immunization Plan in November 2014. The aim of this study is to investigate H. influenzae type b (Hib) carrier rate among children under 6 years old in Tehran. METHODS: This cross-sectional study was performed on 902 children including vaccinated/unvaccinated in the age of 6 months to 6 years, in Tehran. Sampling was performed from July 2019 to September 2019. Nasopharyngeal samples were taken from children by sterile swab. The PCR method was used to extract DNA. Then, all H. influenzae isolates were initially confirmed by molecular tests. BexA was used to distinguish typeable H. influenzae strains from nontypeable Haemophilus influenzae (NTHi). RESULTS: A total of 902 children were enrolled in the study: 452 were female (51%). H. influenzae carriage rate was 267 (29%), of that 150 samples (16.6%) were typeable. The nasopharyngeal Hib carrier rate in the children was 2.6% (24/902). 262 cases did not receive Hib vaccine. Analysis in nonnursery's children aged 4 to 6 (unvaccinated) years showed that the lower educational level of father, mother, and family number correlated with increased odds of colonization of children with Hib. CONCLUSION: Our findings showed a significant decrease (60%) in the overall Hib nasopharyngeal carriage in healthy children under six years after 5 years after the start of Hib vaccination.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine administered concomitantly with other paediatric vaccines in toddlers: a phase III randomised study.

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.

Tralokinumab does not impact vaccine-induced immune responses: Results from a 30-week, randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Interleukin (IL) 13 is a type 2 cytokine that is key to the inflammation underlying AD. Tralokinumab is a first-in-class, fully human, monoclonal antibody that specifically binds with high affinity to IL-13, neutralizing it in AD. Immunomodulatory treatments may impair vaccine-induced immune responses. OBJECTIVE: Assess the immune responses to standard vaccines in adults with moderate-to-severe AD who are undergoing treatment with tralokinumab. METHODS: ECZema TRAlokinumab Trial No. 5 (ECZTRA 5; NCT03562377) was a phase 2, double-blind, randomized, placebo-controlled trial taking place over 30 weeks. Eligible adults were randomized 1:1, with 107 patients receiving tralokinumab 300 mg and 108 patients receiving a placebo every 2 weeks for 16 weeks. All patients received Tdap (tetanus/diphtheria/pertussis) and meningococcal vaccines at week 12. The primary end points were positive antitetanus and antimeningococcal responses between weeks 12 and 16 (noninferiority margin, -25%; responder, >3-fold increase in IgG). RESULTS: The noninferiority of tralokinumab versus placebo for immune response to Tdap (91.9% vs 96.1%) and meningococcal (86.0% vs 84.2%) vaccines was demonstrated at week 16. During treatment, the rates of adverse events were lower for tralokinumab than for the placebo, with most events being mild or moderate. LIMITATIONS: Responses to other vaccines (including influenza) were not examined. CONCLUSIONS: Treatment with tralokinumab 300 mg every 2 weeks did not affect immune responses to Tdap and meningococcal vaccines. Treatment was well tolerated when administered concomitantly with the vaccines and demonstrated a safety profile comparable to phase 3 trials.

Myeloid-derived suppressor cells and their association with vaccine immunogenicity in South African infants.

The role of Myeloid-Derived Suppressor Cells (MDSC) in infant immune ontogeny is unknown. Here, we evaluated MDSC frequency and relationship with infant vaccine responses throughout the first year of life in a prospective cohort study. Ninety-one South African infant-mother pairs were enrolled at delivery, and blood samples were collected at 0, 6, 10, and 14 weeks, 6 months, 9 months, and 1 year. MDSC frequencies were quantified, and immune responses to the childhood vaccines Bacillus Calmette-Guérin (BCG), hepatitis B (HepB), and combination diphtheria, tetanus, and pertussis (dTaP) were measured by Ag-specific CD4+ T cell proliferation and interferon gamma (IFN-γ) production. Vaccine-specific Ab responses to HepB, dTaP, and Haemophilus influenzae type b (Hib) were quantified via Enzyme-Linked Immunosorbent assay (ELISA). MDSC frequency in mother-infant pairs was strongly correlated; the frequency of MDSC decreased in both mothers and infants during the months after delivery/birth; and by 1 year, infant MDSC frequencies rebounded to birth levels. Higher MDSC frequency at vaccination was associated with a lack of subsequent IFN-γ release in response to vaccine Ags, with the exception of BCG. With the exception of a weak, positive correlation between MDSC frequency at 6 weeks (time of initial vaccination) and peak Hepatitis B surface antigen Ab titer, Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSC) was not correlated with T cell proliferation or Ab responses in this study. The potential for MDSC-mediated suppression of vaccine Ag-specific IFN-γ responses should be explored further, and considered when evaluating candidate infant vaccines.

Persistence of Hepatitis B Immune Memory Until 6 Years of Age Following Hexavalent DTaP-IPV-HB-PRP~T Vaccination in a 3-, 5- and 11- to 12-month Schedule and Response to a Subsequent Hepatitis B Challenge Vaccination.

Anti-hepatitis B (HBs) antibody persistence and hepatitis B challenge were evaluated at 6 years of age following vaccination of fully liquid DTaP-IPV-HB-PRP~T or reconstituted DTaP-IPV-HB//PRP~T at 3, 5, 11-12 months of age. At 6 years, 53.8% and 73.5% had seroprotective anti-HBs antibodies (≥10 mIU/mL), increasing to 96.7% and 95.9% postchallenge, confirming a strong anamnestic response in primed vaccinees.

Impacto en niños menores de un año del programa de vacunación con dTpa en embarazadas en Castelló / Impact in children under the age of one of Tdap vaccination programme on pregnant women in Castelló

INTRODUCCIÓN: Se analiza el cambio en las tasas de incidencia de tosferina en menores de un año en Castelló, antes y después de la introducción de la vacunación a embarazadas en enero de 2015. MÉTODOS: Se han comparado las tasas de incidencia del periodo postvacunal (2015-2018) con el prevacunal (2011-2014) en todas las edades, niños de 3 a 11 meses y menores de 3 meses. Se han calculado los riesgos relativos y sus intervalos de confianza al 95%. RESULTADOS: La tasa global fue superior en el periodo postvacunal que en el prevacunal (0,23 vs. 0,15 por 1.000 personas-año), pero disminuyó en los menores de 3 meses. Los riesgos relativos fueron: 1,56 (IC 95% 1,34-1,82) para todas las edades; 1,73 (IC 95% 0,87-3,57) para 3 a 11 meses, y 0,35 (IC 95% 0,16-0,69) para menores de 3 meses. Un patrón similar se observó para niños hospitalizados. CONCLUSIONES: La tasa de incidencia en menores de 3 meses se redujo en un 65%, y el riesgo de hospitalización en un 71%, lo que evidencia que la medida ha sido efectiva. Esta reducción de la incidencia ocurrió de forma específica en este grupo de edad y no en otros

INTRODUCTION: The objective was to compare incidence rates of pertussis in children under the age of one in Castelló, before and after the introduction of vaccination of pregnant women in January 2015. METHODS: The incidence of the post-vaccine period (2015-2018) was compared with the pre-vaccine period (2011-2014) in all ages, in children from 3 to 11 months and under 3 months. The relative risks and their 95% confidence intervals (95% CI) were calculated. RESULTS: The overall rate of pertussis in all ages was higher in the post-vaccine period than in the pre-vaccine period (0.23 vs. 0.15 per 1.000 person-years), but decreased in those under 3 months. The relative risks were: 1.56 (95% CI 1.34-1.82) in all ages; 1.73 (95% CI 0.87-3.57) for children aged 3 to 11 months, and 0.35 (95% CI 0.16-0.69) for children under 3 months. A similar pattern was observed for hospitalised children. CONCLUSIONS: The incidence rate in children under 3 months was reduced by 65% in the period after the intervention, and the hospitalisation risk rate by 71%, suggesting that the measure has been effective and specific for this age group

Potential Cross-Reactive Immunity to SARS-CoV-2 From Common Human Pathogens and Vaccines.

The recently emerged SARS-CoV-2 causing the ongoing COVID-19 pandemic is particularly virulent in the elderly while children are largely spared. Here, we explored the potential role of cross-reactive immunity acquired from pediatric vaccinations and exposure to common human pathogens in the protection and pathology of COVID-19. To that end, we sought for peptide matches to SARS-CoV-2 (identity ≥ 80%, in at least eight residues) in the proteomes of 25 human pathogens and in vaccine antigens, and subsequently predicted their T and B cell reactivity to identify potential cross-reactive epitopes. We found that viruses subject to pediatric vaccinations do not contain cross-reactive epitopes with SARS-CoV-2, precluding that they can provide any general protection against COVID-19. Likewise, common viruses including rhinovirus, respiratory syncytial virus, influenza virus, and several herpesviruses are also poor or null sources of cross-reactive immunity to SARS-CoV-2, discarding that immunological memory against these viruses can have any general protective or pathological role in COVID-19. In contrast, we found combination vaccines for treating diphtheria, tetanus, and pertussis infectious diseases (DTP vaccine) to be significant sources of potential cross-reactive immunity to SARS-CoV-2. DTP cross-reactive epitopes with SARS-CoV-2 include numerous CD8 and CD4 T cell epitopes with broad population protection coverage and potentially neutralizing B cell epitopes in SARS-CoV-2 Spike protein. Worldwide, children receive several DTP vaccinations, including three-four doses the first year of life and one at 4-6 years of age. Moreover, a low antigenic Tdap dose is also given at ages 9-14. Thereby, children may well be protected from SARS-CoV-2 through cross-reactive immunity elicited by DTP vaccinations, supporting testing in the general population to prevent COVID-19.

Gene expression profiling reveals insights into infant immunological and febrile responses to group B meningococcal vaccine.

Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post-vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP-IPV-Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post-vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G-CSF, IL-1RA and IL-6. Post-vaccination fever was associated with increased expression of SELL, involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin-3, -5 and GM-CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine.

Association of Routine Infant Vaccinations With Antibody Levels Among Preterm Infants.

Importance: The standard schedule of national immunization programs for infants may not be sufficient to protect extremely and very preterm infants. Objective: To evaluate the immunogenicity of routine vaccinations administered to preterm infants. Design, Setting, and Participants: A multicenter, prospective, observational cohort study of preterm infants stratified according to gestational age recruited from 8 hospitals across the Netherlands between October 2015 and October 2017, with follow-up until 12 months of age (October 2018). In total, 296 premature infants were enrolled and compared with a control group of 66 healthy term infants from a 2011 study, immunized according to the same schedule with the same vaccines. Exposures: Three primary doses of the diphtheria-tetanus toxoids-acellular pertussis-inactivated poliomyelitis-Haemophilus influenza type b-hepatitis B combination vaccine were given at 2, 3, and 4 months after birth followed by a booster at 11 months and a 10-valent pneumococcal conjugate vaccine at 2, 4, and 11 months after birth. Main Outcomes and Measures: Primary end points were (1) proportion of preterm infants who achieved IgG antibody against vaccine antigens at concentrations above the internationally defined threshold for protection after the primary series and booster dose and (2) serum IgG geometric mean concentrations after the primary series and booster vaccination. Proportions and geometric mean concentrations were compared in preterm infants and the control group of term infants. Results: Of 296 preterm infants (56.1% male; mean gestational age, 30 weeks), complete samples before vaccination, 1 month after the primary series, and 1 month after the booster were obtained from 220 preterm infants (74.3%). After the primary series, the proportion of preterm infants across all gestational age groups who achieved protective IgG antibody levels against pertussis toxin, diphtheria, tetanus and 6 of 10 pneumococcal serotypes varied between 83.0% and 100%, Haemophilus influenzae type b between 34.7% and 46.2% (40.6% among all preterm infants overall), and pneumococcal serotypes 4, 6B, 18C, and 23F between 45.8% and 75.1%. After the booster dose, protective antibody levels were achieved in more than 95% of all preterm groups, except for Haemophilus influenzae type b (88.1%). In general, geometric mean concentrations of all vaccine-induced antibodies were significantly lower in all preterm infants vs term infants, except for pertussis toxin and pneumococcal serotypes 4 and 19F after the primary series and booster vaccination. Conclusions and Relevance: Among preterm infants, administration of routine vaccinations during the first year of life was associated with protective antibody levels against most antigens in the majority of infants after the primary series and booster, except for Haemophilus influenzae type b. However, antibody concentrations were generally lower among preterm infants compared with historical controls.

Pediatric Burn Survivors Have Long-Term Immune Dysfunction With Diminished Vaccine Response.

Epidemiological studies have demonstrated that survivors of acute burn trauma are at long-term increased risk of developing a range of morbidities. The mechanisms underlying this increased risk remain unknown. This study aimed to determine whether burn injury leads to sustained immune dysfunction that may underpin long-term morbidity. Plasma and peripheral blood mononuclear cells were collected from 36 pediatric burn survivors >3 years after a non-severe burn injury (<10% total body surface area) and from age/sex-matched non-injured controls. Circulating cytokine and vaccine antibody levels were assessed using multiplex immunoassays and cell profiles compared using a panel of 40 metal-conjugated antibodies and mass cytometry. TNF-α (1.31-fold change from controls), IL-2 (1.18-fold), IL-7 (1.63-fold), and IFN-γ (1.18-fold) were all significantly elevated in the burn cohort. Additionally, burn survivors demonstrated diminished antibody responses to the diphtheria, tetanus, and pertussis vaccine antigens. Comparisons between groups using unsupervised clustering identified differences in proportions of clusters within T-cells, B-cells and myeloid cells. Manual gating confirmed increased memory T-regulatory and central memory CD4+ T-cells, with altered expression of T-cell, B-cell, and dendritic cell markers. Conclusions: This study demonstrates a lasting change to the immune profile of pediatric burn survivors, and highlights the need for further research into post-burn immune suppression and regulation.

Limited Impact of Human Cytomegalovirus Infection in African Infants on Vaccine-Specific Responses Following Diphtheria-Tetanus-Pertussis and Measles Vaccination.

Human cytomegalovirus (HCMV) infection has a profound effect on the human immune system, causing massive clonal expansion of CD8, and to a lesser extend CD4 T cells. The few human trials that have explored the effect of HCMV infection on responses to vaccination are conflicting, with some studies suggesting no effect whilst others suggest decreased or increased immune responses. Recent studies indicate substantial differences in overall immune system reactivity to vaccines based on age and sex, particularly cellular immunity. 225 nine-month old Gambian infants were immunized with diphtheria-tetanus-whole cell pertussis and/or measles vaccines. HCMV infection status was determined by the presence of CMV DNA by PCR of urine samples prior to vaccination. The effect of HCMV infection on either protective antibody immunity or vaccine-specific and overall cellular immune responses 4 weeks post-vaccination was determined, further stratified by sex. Tetanus toxoid-specific antibody responses were significantly lower in HCMV+ infants compared to their HCMV- counterparts, while pertussis, diphtheria and measles antibody responses were generally comparable between the groups. Responses to general T cell stimulation with anti-CD3/anti-CD28 as well as antigen-specific cytokine responses to purified protein derivative (PPD) were broadly suppressed in infants infected with HCMV but, perhaps surprisingly, there was only a minimal impact on antigen-specific cellular responses to vaccine antigens. There was evidence for subtle sex differences in the effects of HCMV infection, in keeping with the emerging evidence suggesting sex differences in homeostatic immunity and in responses to vaccines. This study reassuringly suggests that the high rates of HCMV infection in low income settings have little clinically significant impact on antibody and cellular responses to early life vaccines, while confirming the importance of sex stratification in such studies.