ABSTRACT
BACKGROUND: Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. METHODS: We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2-3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2-3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-µg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-µg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 µg of BNT162b2 in the pivotal trial. RESULTS: During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-µg dose) and 48 children 2 to 4 years of age (3-µg or 10-µg dose). The 3-µg dose level was selected for the phase 2-3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). CONCLUSIONS: A three-dose primary series of 3-µg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).
Subject(s)
BNT162 Vaccine , COVID-19 , Adolescent , Child , Child, Preschool , Humans , Infant , Young Adult , Antibodies, Viral/blood , Antibodies, Viral/immunology , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/adverse effects , BNT162 Vaccine/immunology , BNT162 Vaccine/therapeutic use , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Immunoglobulin G/blood , Immunoglobulin G/immunology , Vaccines/adverse effects , Vaccines/therapeutic use , Immunogenicity, Vaccine , Treatment Outcome , Vaccine EfficacyABSTRACT
BACKGROUND: Safe, effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in children younger than 12 years of age. METHODS: A phase 1, dose-finding study and an ongoing phase 2-3 randomized trial are being conducted to investigate the safety, immunogenicity, and efficacy of two doses of the BNT162b2 vaccine administered 21 days apart in children 6 months to 11 years of age. We present results for 5-to-11-year-old children. In the phase 2-3 trial, participants were randomly assigned in a 2:1 ratio to receive two doses of either the BNT162b2 vaccine at the dose level identified during the open-label phase 1 study or placebo. Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-µg doses of BNT162b2. Vaccine efficacy against Covid-19 at 7 days or more after the second dose was assessed. RESULTS: During the phase 1 study, a total of 48 children 5 to 11 years of age received 10 µg, 20 µg, or 30 µg of the BNT162b2 vaccine (16 children at each dose level). On the basis of reactogenicity and immunogenicity, a dose level of 10 µg was selected for further study. In the phase 2-3 trial, a total of 2268 children were randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). At data cutoff, the median follow-up was 2.3 months. In the 5-to-11-year-olds, as in other age groups, the BNT162b2 vaccine had a favorable safety profile. No vaccine-related serious adverse events were noted. One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). Covid-19 with onset 7 days or more after the second dose was reported in three recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3). CONCLUSIONS: A Covid-19 vaccination regimen consisting of two 10-µg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).
ABSTRACT
BACKGROUND: Safe and effective respiratory syncytial virus (RSV) vaccines remain elusive. This was a phase I/II trial (NCT02927873) of ChAd155-RSV, an investigational chimpanzee adenovirus-RSV vaccine expressing 3 proteins (fusion, nucleoprotein, and M2-1), administered to 12-23-month-old RSV-seropositive children followed up for 2 years after vaccination. METHODS: Children were randomized to receive 2 doses of ChAd155-RSV or placebo (at a 1:1 ratio) (days 1 and 31). Doses escalated from 0.5 × 1010 (low dose [LD]) to 1.5 × 1010 (medium dose [MD]) to 5 × 1010 (high dose [HD]) viral particles after safety assessment. Study end points included anti-RSV-A neutralizing antibody (Nab) titers through year 1 and safety through year 2. RESULTS: Eighty-two participants were vaccinated, including 11, 14, and 18 in the RSV-LD, RSV-MD, and RSV-HD groups, respectively, and 39 in the placebo groups. Solicited adverse events were similar across groups, except for fever (more frequent with RSV-HD). Most fevers were mild (≤38.5°C). No vaccine-related serious adverse events or RSV-related hospitalizations were reported. There was a dose-dependent increase in RSV-A Nab titers in all groups after dose 1, without further increase after dose 2. RSV-A Nab titers remained higher than prevaccination levels at year 1. CONCLUSIONS: Three ChAd155-RSV dosages were found to be well tolerated. A dose-dependent immune response was observed after dose 1, with no observed booster effect after dose 2. Further investigation of ChAd155-RSV in RSV-seronegative children is warranted. CLINICAL TRIALS REGISTRATION: NCT02927873.
Respiratory syncytial virus (RSV) is among the main causes of bronchiolitis and pneumonia regularly leading to hospitalization in children. A safe and effective vaccine to prevent RSV infection in this age group has not yet been found, despite great efforts over several decades. This study tested a new candidate RSV vaccine, expressing 3 important pieces of the virus, in toddlers who already had a previous RSV infection. The vaccine was generally well tolerated. Vaccination triggered antibodies against RSV that were able to block the virus in laboratory tests and that persisted for 1 year.
Subject(s)
Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus Vaccines , Respiratory Syncytial Virus, Human , Humans , Infant , Antibodies, Neutralizing , Antibodies, Viral , Respiratory Syncytial Virus, Human/geneticsABSTRACT
BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose. METHODS: In this trial conducted in both northern and southern hemispheres, we evaluated nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation). We randomly assigned the infants in a 2:1 ratio to receive nirsevimab, at a dose of 50 mg in a single intramuscular injection, or placebo at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose. RESULTS: From November 2016 through November 2017, a total of 1453 infants were randomly assigned to receive nirsevimab (969 infants) or placebo (484 infants) at the start of the RSV season. The incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower (95% confidence interval [CI], 52.3 to 81.2) with nirsevimab prophylaxis than with placebo (2.6% [25 infants] vs. 9.5% [46 infants]; P<0.001) and the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower (95% CI, 51.9 to 90.3) with nirsevimab than with placebo (0.8% [8 infants] vs. 4.1% [20 infants]; P<0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions. CONCLUSIONS: A single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants. (Funded by AstraZeneca and Sanofi Pasteur; ClinicalTrials.gov number, NCT02878330.).
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal/administration & dosage , Antiviral Agents/administration & dosage , Infant, Premature , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus, Human , Respiratory Tract Infections/prevention & control , Viral Fusion Proteins/antagonists & inhibitors , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Antiviral Agents/adverse effects , Female , Hospitalization/statistics & numerical data , Humans , Incidence , Infant , Infant, Newborn , Injections, Intramuscular , Kaplan-Meier Estimate , Male , Poisson Distribution , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/virologyABSTRACT
BACKGROUND: The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life. METHODS: This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods. RESULTS: Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88-9.08), 5.50 (95% CI, 4.21-7.07), and 2.87 (95% CI, 2.18-3.70) cases/100 person-years in children aged 0-5, 6-11, and 12-23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0-5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0-2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs. CONCLUSIONS: A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175.
Subject(s)
Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Respiratory Tract Infections , Viruses , Child , Hospitalization , Humans , Incidence , Infant , Prospective StudiesABSTRACT
OBJECTIVE: The SENTINEL1 observational study characterized confirmed respiratory syncytial virus hospitalizations (RSVH) among U.S. preterm infants born at 29 to 35 weeks' gestational age (wGA) not receiving respiratory syncytial virus (RSV) immunoprophylaxis (IP) during the 2014 to 2015 and 2015 to 2016 RSV seasons. STUDY DESIGN: All laboratory-confirmed RSVH at participating sites during the 2014 to 2015 and 2015 to 2016 RSV seasons (October 1-April 30) lasting ≥24 hours among preterm infants 29 to 35 wGA and aged <12 months who did not receive RSV IP within 35 days before onset of symptoms were identified and characterized. RESULTS: Results were similar across the two seasons. Among infants with community-acquired RSVH (N = 1,378), 45% were admitted to the intensive care unit (ICU) and 19% required invasive mechanical ventilation (IMV). There were two deaths. Infants aged <6 months accounted for 78% of RSVH observed, 84% of ICU admissions, and 91% requiring IMV. Among infants who were discharged from their birth hospitalization during the RSV season, 82% of RSVH occurred within 60 days of birth hospitalization discharge. CONCLUSION: Among U.S. preterm infants 29 to 35 wGA not receiving RSV IP, RSVH are often severe with almost one-half requiring ICU admission and about one in five needing IMV.
Subject(s)
Hospitalization/statistics & numerical data , Infant, Premature, Diseases/epidemiology , Infant, Premature , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus, Human , Antiviral Agents/therapeutic use , Community-Acquired Infections/epidemiology , Female , Humans , Infant , Infant, Newborn , Infant, Premature, Diseases/prevention & control , Infant, Premature, Diseases/therapy , Intensive Care Units, Pediatric , Male , Multivariate Analysis , Odds Ratio , Palivizumab/therapeutic use , Respiration, Artificial , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/therapy , United States/epidemiologyABSTRACT
OBJECTIVE: To develop a program to educate providers, office staff, patients, and parents on life-long cancer prevention strategies, including the use of human papillomavirus (HPV) vaccine to improve adolescent HPV vaccination rates. STUDY DESIGN: A 2-phase program was implemented at 6 pediatric practices across upstate New York. Phase 1 included provider and staff education regarding practice-specific vaccination challenges and discussion of the contents of a study-specific cancer-prevention booklet, which included HPV vaccine information. Throughout phase 2, the booklets were distributed to all adolescents and their parents during office visits over a 12-month period. Practice-specific, countywide, and statewide HPV vaccination rates were assessed before phase 1, and 6 and 12 months after the launch of phase 2. RESULTS: One year after implementing phase 2 in 6 practices, adolescent HPV vaccine series initiation increased by at least 10% in 3 practices, and at least 5% in 5 practices. Similarly, adolescent vaccine series completion rates increased by more than 10% in 3 practices. The percent change in vaccine series completion rates across all study sites postintervention ranged from 12% to 20% for 11- to 12-year-olds, and from 7% to 23% for 13- to 18-year-olds. CONCLUSIONS: Cancer prevention education targeting providers, office staff, patients, and parents was modestly effective for improving adolescent HPV vaccination rates.
Subject(s)
Health Education/methods , Health Personnel/education , Immunization/statistics & numerical data , Neoplasms/prevention & control , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/pharmacology , Parents/education , Adolescent , Child , Female , Humans , Male , Patient Education as Topic , Program Development , Retrospective Studies , United StatesABSTRACT
Background: Respiratory syncytial virus (RSV) causes bronchiolitis and pneumonia in neonates and infants. RSV vaccination during pregnancy could boost preexisting neutralizing antibody titers, providing passive protection to newborns. Methods: Two observer-blinded, controlled studies (RSV F-020 [clinical trials registration NCT02360475] and RSV F-024 [NCT02753413]) evaluated immunogenicity and safety of an investigational RSV vaccine in healthy, nonpregnant 18-45-year-old women. Both studies used a licensed adult formulation of combined tetanus toxoid-diphtheria toxoid-acellular pertussis (Tdap) vaccine as a control. RSV F-020 evaluated immunogenicity and safety: participants were randomized (1:1:1:1) to receive 1 dose of RSV-prefusion F protein (PreF) vaccine containing 30 µg or 60 µg of nonadjuvanted RSV-PreF, 60 µg of aluminum-adjuvanted RSV-PreF, or Tdap. RSV F-024 evaluated safety: participants were randomized 1:1 to receive 1 dose of 60 µg of nonadjuvanted RSV-PreF or Tdap. Results: Both studies showed similar reactogenicity profiles for RSV-PreF and Tdap. No serious adverse events were considered vaccine related. In RSV F-020, geometric mean ratios of RSV-A neutralizing antibody levels at day 30 versus prevaccination were 3.1-3.9 in RSV-PreF recipients and 0.9 in controls. Palivizumab-competing antibody concentrations increased >14-fold in RSV-PreF recipients on day 30. RSV antibody titers waned after day 30 but remained well above baseline through day 90. Conclusions: All formulations of RSV-PreF boosted preexisting immune responses in 18-45-year old women with comparable immunogenicity. The RSV-PreF safety profile was similar to that of Tdap vaccine.
Subject(s)
Immunogenicity, Vaccine/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Vaccines/adverse effects , Respiratory Syncytial Virus Vaccines/immunology , Respiratory Syncytial Virus, Human/immunology , Adjuvants, Immunologic/pharmacology , Adolescent , Adult , Antibodies, Bacterial/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Diphtheria-Tetanus-Pertussis Vaccine/immunology , Diphtheria-Tetanus-acellular Pertussis Vaccines/immunology , Female , Humans , Middle Aged , Vaccination/methods , Whooping Cough/immunology , Young AdultABSTRACT
Objective SENTINEL1 characterized U.S. preterm infants 29 to 35 weeks' gestational age (wGA) < 12 months old hospitalized for laboratory-confirmed respiratory syncytial virus (RSV) disease and not receiving RSV immunoprophylaxis during the 2014 to 2015 RSV season. Study Design This is a noninterventional, observational, cohort study. Results A total of 702 infants were hospitalized with community-acquired RSV disease, of whom an estimated 42% were admitted to the intensive care unit (ICU) and 20% required invasive mechanical ventilation (IMV). Earlier gestational age and younger chronologic age were associated with an increased frequency of RSV-confirmed hospitalization (RSVH), ICU admission, and IMV. Among infants 29 to 32 wGA and < 3 months of age, 68% required ICU admission and 44% required IMV. One death occurred of an infant 29 wGA. Among the 212 infants enrolled for in-depth analysis of health care resource utilization, mean and median RSVH charges were $55,551 and $27,461, respectively, which varied by intensity of care required. Outpatient visits were common, with 63% and 62% of infants requiring visits before and within 1 month following the RSVH, respectively. Conclusion Preterm infants 29 to 35 wGA are at high risk for severe RSV disease, which imposes a substantial health burden, particularly in the first months of life.
Subject(s)
Ambulatory Care/statistics & numerical data , Hospital Costs , Hospitalization/statistics & numerical data , Respiratory Syncytial Virus Infections/epidemiology , Ambulatory Care/economics , Antiviral Agents/therapeutic use , Cohort Studies , Female , Gestational Age , Health Care Costs , Humans , Infant , Infant, Newborn , Infant, Premature , Intensive Care Units, Pediatric , Male , Palivizumab/therapeutic use , Respiration, Artificial , Respiratory Syncytial Virus Infections/prevention & control , United States/epidemiologyABSTRACT
Eosinophils are recruited to the airways as a prominent feature of the asthmatic inflammatory response where they are broadly perceived as promoting pathophysiology. Respiratory virus infections exacerbate established asthma; however, the role of eosinophils and the nature of their interactions with respiratory viruses remain uncertain. To explore these questions, we established acute infection with the rodent pneumovirus, pneumonia virus of mice (PVM), in 3 distinct mouse models of Th2 cytokine-driven asthmatic inflammation. We found that eosinophils recruited to the airways of otherwise naïve mice in response to Aspergillus fumigatus, but not ovalbumin sensitization and challenge, are activated by and degranulate specifically in response to PVM infection. Furthermore, we demonstrate that activated eosinophils from both Aspergillus antigen and cytokine-driven asthma models are profoundly antiviral and promote survival in response to an otherwise lethal PVM infection. Thus, although activated eosinophils within a Th2-polarized inflammatory response may have pathophysiologic features, they are also efficient and effective mediators of antiviral host defense.
Subject(s)
Eosinophils/immunology , Lung/immunology , Lung/virology , Murine pneumonia virus/immunology , Pneumovirus Infections/immunology , Animals , Aspergillus fumigatus/immunology , Asthma/immunology , Asthma/microbiology , Cell Degranulation , Eosinophils/physiology , Eosinophils/virology , Female , Male , Mice , Mice, Inbred C57BL , Ovalbumin/immunologyABSTRACT
We have shown previously that priming of respiratory mucosa with live Lactobacillus species promotes robust and prolonged survival from an otherwise lethal infection with pneumonia virus of mice, a property known as heterologous immunity. Lactobacillus priming results in a moderate reduction in virus recovery and a dramatic reduction in virus-induced proinflammatory cytokine production; the precise mechanisms underlying these findings remain to be elucidated. Because B cells have been shown to promote heterologous immunity against respiratory virus pathogens under similar conditions, in this study we explore the role of B cells in Lactobacillus-mediated protection against acute pneumovirus infection. We found that Lactobacillus-primed mice feature elevated levels of airway Igs IgG, IgA, and IgM and lung tissues with dense, B cell (B220(+))-enriched peribronchial and perivascular infiltrates with germinal centers consistent with descriptions of BALT. No B cells were detected in lung tissue of Lactobacillus-primed B cell deficient µMT mice or Jh mice, and Lactobacillus-primed µMT mice had no characteristic infiltrates or airway Igs. Nonetheless, we observed diminished virus recovery and profound suppression of virus-induced proinflammatory cytokines CCL2, IFN-γ, and CXCL10 in both wild-type and Lactobacillus-primed µMT mice. Furthermore, Lactobacillus plantarum-primed, B cell-deficient µMT and Jh mice were fully protected from an otherwise lethal pneumonia virus of mice infection, as were their respective wild-types. We conclude that B cells are dispensable for Lactobacillus-mediated heterologous immunity and were not crucial for promoting survival in response to an otherwise lethal pneumovirus infection.
Subject(s)
B-Lymphocytes/immunology , Lactobacillus/immunology , Lung/immunology , Pneumovirus Infections/immunology , Pneumovirus/immunology , Respiratory Mucosa/immunology , Animals , Antibodies, Bacterial/genetics , Antibodies, Bacterial/immunology , Cytokines/genetics , Cytokines/immunology , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Pneumovirus/genetics , Pneumovirus Infections/genetics , Pneumovirus Infections/pathology , Respiratory Mucosa/pathology , Respiratory Mucosa/virologyABSTRACT
IL-21 is a cytokine with pleiotropic actions, promoting terminal differentiation of B cells, increased Ig production, and the development of Th17 and T follicular helper cells. IL-21 is also implicated in the development of autoimmune disease and has antitumor activity. In this study, we investigated the role of IL-21 in host defense to pneumonia virus of mice (PVM), which initiates an infection in mice resembling that of respiratory syncytial virus disease in humans. We found that PVM-infected mice expressed IL-21 in lung CD4(+) T cells. Following infection, Il21r(-/-) mice exhibited less lung infiltration by neutrophils than did wild-type (WT) mice and correspondingly had lower levels of the chemokine CXCL1 in bronchoalveolar lavage fluid and lung parenchyma. CD8(+), CD4(+), and γδ T cell numbers were also lower in the lungs of PVM-infected Il21r(-/-) mice than in infected WT mice, with normal Th17 cytokines but diminished IL-6 production in PVM-infected Il21r(-/-) mice. Strikingly, Il21r(-/-) mice had enhanced survival following PVM infection, and moreover, treatment of WT mice with soluble IL-21R-Fc fusion protein enhanced their survival. These data reveal that IL-21 promotes the pathogenic inflammatory effect of PVM and indicate that manipulating IL-21 signaling may represent an immunomodulatory strategy for controlling PVM and potentially other respiratory virus infections.
Subject(s)
Interleukins/immunology , Murine pneumonia virus/immunology , Pneumovirus Infections/immunology , Pneumovirus Infections/pathology , Animals , Bronchoalveolar Lavage Fluid/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Chemokine CXCL1/biosynthesis , Chemokine CXCL1/immunology , Interleukin-6/biosynthesis , Interleukin-6/deficiency , Interleukins/biosynthesis , Interleukins/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Murine pneumonia virus/pathogenicity , Receptors, Interleukin-21/immunology , Th17 Cells/immunologyABSTRACT
BACKGROUND: Two antigenically distinct influenza B lineages have cocirculated since 2001, yet trivalent influenza vaccines (TIVs) contain 1 influenza B antigen, meaning lineage mismatch with the vaccine is frequent. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages vs TIV in healthy children aged 3-17 years. METHODS: Children were randomized 1:1:1 to receive QIV or 1 of 2 TIVs (either B/Victoria or B/Yamagata lineage; N = 2738). Hemagglutination-inhibition assays were performed 28 days after 1 or 2 doses in primed and unprimed children, respectively. Immunological noninferiority of QIV vs TIV against shared strains, and superiority against alternate-lineage B strains was based on geometric mean titers (GMTs) and seroconversion rates. Reactogenicity and safety were also assessed (Clinicaltrials.gov NCT01196988). RESULTS: Noninferiority against shared strains and superiority against alternate-lineage B strains was demonstrated for QIV vs TIV. QIV was highly immunogenic; seroconversion rates were 91.4%, 72.3%, 70.0%, and 72.5% against A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, respectively. Reactogenicity and safety of QIV was consistent with TIV. CONCLUSIONS: QIV vs TIV showed superior immunogenicity for the additional B strain without interfering with immune responses to shared strains. QIV may offer improved protection against influenza B in children compared with current trivalent vaccines.
Subject(s)
Antibodies, Viral/immunology , Influenza A virus/immunology , Influenza B virus/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Adolescent , Antibodies, Viral/biosynthesis , Child , Child, Preschool , Cohort Studies , Double-Blind Method , Europe , Female , HIV Seropositivity , Hemagglutination Inhibition Tests , Humans , Infant , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H3N2 Subtype/immunology , Influenza, Human/virology , Male , Philippines , Safety , United States , Vaccination , Vaccines, InactivatedABSTRACT
The United States (U.S.) Food and Drug Administration (FDA) oversees the safety and quality of drugs and vaccines that are used in the U.S. Administration of the FDA falls under the jurisdiction of the U.S. Department of Health and Human Services (HHS). The regulatory oversight of the FDA is complex and comprehensive, requiring the various roles and responsibilities to be divided across six main centers. The activities of two of these centers, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are the primary focus of this review.
Subject(s)
Drug Approval , United States Food and Drug Administration , Vaccines , United States , Drug Approval/legislation & jurisprudence , Humans , Vaccines/therapeutic use , Drug Development/legislation & jurisprudence , United States Dept. of Health and Human ServicesABSTRACT
To date, safe and effective strategies to prevent medically attended respiratory syncytial virus (RSV) illness across the infant population have been limited to passive immunoprophylaxis for those at highest risk. While active vaccination strategies are finally available to protect adults 60 years and older from serious RSV infection, safe and effective vaccines for use in children have yet to emerge. In contrast, passive immunization strategies designed to protect all infants against RSV has finally met with success, with 2 new strategies approved by the US Food and Drug Administration during the second half of 2023. The first RSV passive immunization strategy to gain licensure for use in all infants is an extended half-life monoclonal antibody directed against an antigenic binding site on the RSV-F prefusion protein, a conformation not known to exist until 2013. The second novel passive immunization strategy approved during 2023 that has the potential to protect much of the infant population from RSV during young infancy centers on boosting preexisting RSV immunity during pregnancy using a prefusion RSV-F vaccine. The resulting boosted humoral immune response to RSV in the mother becomes part of the transplacental antibody endowment that is actively transported across the placenta to provide protection to those babies born at or near term. This review describes how and why these advances came to fruition seemingly "all at once" and provides insight into other passive immunization approaches that remain under development.
Subject(s)
Immunization, Passive , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus Vaccines , Humans , Immunization, Passive/methods , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/immunology , Infant , Respiratory Syncytial Virus Vaccines/immunology , Respiratory Syncytial Virus Vaccines/administration & dosage , Female , Pregnancy , Respiratory Syncytial Virus, Human/immunology , Antibodies, Viral , Antibodies, Monoclonal/immunology , Immunity, Maternally-AcquiredABSTRACT
BACKGROUND: There is limited evidence regarding the proportion of wheeze in young children attributable to respiratory syncytial virus lower respiratory tract infections (RSV-LRTI) occurring early in life. This cohort study prospectively determined the population attributable risk (PAR) and risk percent (PAR%) of wheeze in 2-<6-year-old children previously surveilled in a primary study for RSV-LRTI from birth to their second birthday (RSV-LRTI<2Y). METHODS: From 2013 to 2021, 2-year-old children from 8 countries were enrolled in this extension study (NCT01995175) and were followed through quarterly surveillance contacts until their sixth birthday for the occurrence of parent-reported wheeze, medically-attended wheeze or recurrent wheeze episodes (≥4 episodes/year). PAR% was calculated as PAR divided by the cumulative incidence of wheeze in all participants. RESULTS: Of 1395 children included in the analyses, 126 had documented RSV-LRTI<2Y. Cumulative incidences were higher for reported (38.1% vs. 13.6%), medically-attended (30.2% vs. 11.8%) and recurrent wheeze outcomes (4.0% vs. 0.6%) in participants with RSV-LRTI<2Y than those without RSV-LRTI<2Y. The PARs for all episodes of reported, medically-attended and recurrent wheeze were 22.2, 16.6 and 3.1 per 1000 children, corresponding to PAR% of 14.1%, 12.3% and 35.9%. In univariate analyses, all 3 wheeze outcomes were strongly associated with RSV-LRTI<2Y (all global P < 0.01). Multivariable modeling for medically-attended wheeze showed a strong association with RSV-LRTI after adjustment for covariates (global P < 0.0001). CONCLUSIONS: A substantial amount of wheeze from the second to sixth birthday is potentially attributable to RSV-LRTI<2Y. Prevention of RSV-LRTI<2Y could potentially reduce wheezing episodes in 2-<6-year-old children.
ABSTRACT
BACKGROUND: Using a murine model of parainfluenza virus infection (mPIV1 or Sendai virus; SeV), we compared the inflammatory responses to lethal and sub-lethal infections in inbred DBA/2 mice. METHODS: Mice were intranasally inoculated with either 1.6×10(3) or 1.6×10(5) infectious units (IU) of SeV or diluent control. Clinical data including daily weights, oxygen saturation, and lung function via whole body plethysmography were collected on days 0, 3-7, and 9-14. Clarified whole lung homogenates were evaluated for inflammatory markers by enzyme-linked immunoassay (ELISA). Data were analyzed using ANOVA or Student t-tests, as appropriate. RESULTS: Mice inoculated with 1.6×10(5) IU of SeV developed a lethal infection with 100% mortality by day 7, while mice inoculated with 1.6×10(3) IU developed a clinically significant infection, with universal weight loss but only 32% mortality. Interestingly, peak virus recovery from the lungs of mice inoculated with 1.6×10(5) IU of SeV did not differ substantially from that detected in mice that received the 100-fold lower inoculum. In contrast, concentrations of CCL5 (RANTES), CCL11 (eotaxin), interferon-γ, CXCL10 (IP-10), and CCL3 (MIP-1α) were significantly higher in lung tissue homogenates from mice inoculated with 1.6×105 IU (p < 0.05). In the lethal infection, levels of CCL11, interferon- γ and CCL3 all correlated strongly with disease severity. CONCLUSION: We observed that severity of SeV-infection in DBA/2 mice was not associated with virus recovery but rather with the levels of proinflammatory cytokines, specifically CCL11, interferon- γ and CCL3, detected in lung tissue in response to SeV infection.
Subject(s)
Chemokine CCL11/metabolism , Chemokine CCL3/metabolism , Interferon-gamma/metabolism , Paramyxoviridae Infections/immunology , Paramyxoviridae Infections/pathology , Animals , Body Weight , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Inflammation/pathology , Lung/pathology , Mice , Mice, Inbred DBA , Oxygen/blood , Plethysmography , Respiratory Function TestsABSTRACT
The inflammatory response to respiratory virus infection can be complex and refractory to standard therapy. Lactobacilli, when targeted to the respiratory epithelium, are highly effective at suppressing virus-induced inflammation and protecting against lethal disease. Specifically, wild-type mice primed via intranasal inoculation with live or heat-inactivated Lactobacillus plantarum or Lactobacillus reuteri were completely protected against lethal infection with the virulent rodent pathogen, pneumonia virus of mice; significant protection (60% survival) persisted for at least 13 wk. Protection was not unique to Lactobacillus species, and it was also observed in response to priming with nonpathogenic Gram-positive Listeria innocua. Priming with live lactobacilli resulted in diminished granulocyte recruitment, diminished expression of multiple proinflammatory cytokines (CXCL10, CXCL1, CCL2, and TNF), and reduced virus recovery, although we have demonstrated clearly that absolute virus titer does not predict clinical outcome. Lactobacillus priming also resulted in prolonged survival and protection against the lethal sequelae of pneumonia virus of mice infection in MyD88 gene-deleted (MyD88(-/-)) mice, suggesting that the protective mechanisms may be TLR-independent. Most intriguing, virus recovery and cytokine expression patterns in Lactobacillus-primed MyD88(-/-) mice were indistinguishable from those observed in control-primed MyD88(-/-) counterparts. In summary, we have identified and characterized an effective Lactobacillus-mediated innate immune shield, which may ultimately serve as critical and long-term protection against infection in the absence of specific antiviral vaccines.
Subject(s)
Lactobacillus plantarum/immunology , Limosilactobacillus reuteri/immunology , Murine pneumonia virus/immunology , Pneumovirus Infections/mortality , Pneumovirus Infections/prevention & control , Respiratory Mucosa/immunology , Respiratory Mucosa/microbiology , Administration, Intranasal , Animals , Antigens, Viral/metabolism , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Murine pneumonia virus/pathogenicity , Pneumovirus Infections/immunology , Respiratory Mucosa/virology , Virus Replication/immunologyABSTRACT
Community-wide vaccine uptake remains sub-optimal. Healthcare provider (HCP) vaccine recommendations influence patient vaccination; however, provider vaccine recommendation behavior is highly influenced by one's own vaccine attitudes and/or knowledge. We aim to describe vaccine knowledge, attitudes, and recommendation practices (KAP) among New York State HCPs. A survey to assess HCP KAP was developed and electronically distributed to NYS members of national medical organizations via their local chapter administrators. Descriptive statistical methods were used to define provider KAP. A total of 864 surveys were included, 500 (60%) and 336 (40%) primary and specialty care providers, respectively. Eighty-one percent (402/499) of primary care providers (PCPs) report encountering vaccine hesitant patients daily or weekly. Of the 500 PCPs who responded, only 204 (41%) stated strong agreement with confidence in their communications with vaccine hesitant patients. HCPs who correctly answered all four knowledge questions were more likely to self-report routine recommendations of standard vaccines to all patients when compared to those who correctly answered fewer questions (489/588 (83%) vs 135/241 (56%), p < .05). HCPs were more likely to routinely recommend standard vaccines to all patients if they also report initiating vaccine discussion (476/485 (98%) vs 148/344 (43%), p < .05) and reviewing and recommending vaccinations at each encounter (315/320 (98%) vs 308/508 (61%), p < .05). Vaccine hesitancy exists across healthcare specialties and provider roles. Focused interventions should include reaching all HCPs to promote vaccinations for disease prevention, tailoring messages to reduce HCP vaccine misperceptions, and increasing awareness of evidence-based office strategies known to facilitate immunizations.
Subject(s)
Health Knowledge, Attitudes, Practice , Vaccines , Humans , New York , Vaccination , Health PersonnelABSTRACT
Healthcare provider vaccine knowledge and attitudes influence delivery of a strong vaccine recommendation. We aim to describe HPV vaccine knowledge, attitudes, and recommendation or discussion practices (KAP) among New York State medical providers, dentists, and pharmacists. A survey to assess providers' KAP was distributed electronically to NYS members of medical organizations. Descriptive and inferential statistical methods were used to characterize provider KAP. Responses from 1637 surveys were included, from 864 (53%) medical providers, 737 (45%) dentists, and 36 (2%) pharmacists. 59% (509/864) of medical providers responded that they recommend HPV vaccine to patients, with 390/509 (77%) strongly recommending vaccine at 11-12 years. Medical providers were more likely to report recommending HPV vaccine for children ages 11-12 years if they strongly agreed that HPV vaccine prevents cancer 326/391 (83%) vs 64/117 (55%) and responded that HPV vaccination does not increase the risk of unprotected sex (386/494 (78%) vs 4/15 (25%)) (p < .05). Less than 1/3 of dentists reported discussing HPV vaccine with 11-26-year-old females (230/737, 31%) and males (205/737, 28%) at least "sometimes." Dentists were more likely to answer that they routinely discuss HPV vaccine with children ages 11-12 years if they responded that HPV vaccination does not increase sexual activity (70/73 (96%) vs 528/662 (80%), p < .001). Few pharmacists reported discussing HPV vaccine with 11-26-year-old females (6/36 (17%)) and males (5/36 (14%)) at least "sometimes." Gaps in HPV vaccine knowledge among providers still exist and may influence vaccine attitudes and recommendation or discussion practices.