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Background: Respiratory syncytial virus (RSV) fusion protein stabilized in the prefusion conformation (RSVPreF3) was under investigation as a maternal vaccine., Methods: This phase 2, randomized, placebo-controlled, single-dose, multicenter study enrolled healthy, nonpregnant women, randomized 1:1:1:1:1 to 5 parallel groups studying RSVPreF3 (60 or 120 µg) coadministered with diphtheria, tetanus, and acellular pertussis vaccine (dTpa) or placebo, and dTpa coadministered with placebo. Safety and humoral immune responses were assessed. An extension phase also assessed a RSVPreF3 120 μg vaccination 12-18 months after first vaccination., Results: The safety profile of RSVPreF3 was unaffected by dose or dTpa coadministration. Solicited and unsolicited adverse events (AEs) were evenly distributed across study groups. Injection-site pain was higher following the second vaccination versus the first vaccination. Medically attended AEs were rare (<5% overall). Both RSVPreF3 dose levels (alone and with dTpa) were immunogenic, increasing levels of RSV-A neutralizing antibody ≥8-fold and anti-RSVPreF3 IgG antibody ≥11-fold at 1 month postvaccination, which persisted at 12-18 months postvaccination; modest 2-fold increases were observed with a second RSVPreF3 vaccination., Conclusions: This study indicates RSVPreF3 coadministration with dTpa induces robust immune responses and is well tolerated, regardless of the RSVPreF3 dose level used., Clinical Trials Registration: NCT04138056., Competing Interests: Potential conflicts of interest. N. He., D. Y., N. Hu., P. v. d. S., I. L., and J. H. K. are GSK employees. P. v. d. S., B. A., I. L., and J. H. K. receive GSK shares/stock options as part of their employee remuneration. M. F. received a salary as principal investigator for the Colchester Research Group which he co-owns with his wife, Dr Linda Ferguson, and which took part in this study. I. L.-R. received fees from GSK for conducting the present work; their institution has received grants from Virometix and Icosavax; and has received personal fees from Janssen for participating in an Advisory Board. S. P. has no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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., Competing Interests: E.L., A.T., B.A., E.C., J.A.C., I.D., S.G., J.H.K., R.M., M.O.O., S.K.S. and R.A.C. are/were employees of GSK. E.L., B.A., I.D., S.G., J.H.K., S.K.S. and R.A.C. hold/held GSK shares. S.A.M. declares receiving GSK funding to his institution for the conduct of the study, grants to his institution from Bill & Melinda Gates Foundation, GSK, Pfizer, and MinervaX, clinical trial funding to institution from Novavax, Merck, Providence Therapeutics, Gritstone bio, and ImmunityBio, and GSK payment honoraria for lectures. He was also Chair of Data Safety Monitoring Board for PATH (rotavirus vaccine) and CAPRISA (HIV monoclonal antibody). J.M.L. received GSK funding to Dalhousie University, received grants or contracts from GSK, Pfizer, Merck, and Moderna, and consulting fees from GSK. The author declares other financial or nonfinancial interests as expert panelist for the Canadian Agency for Drugs and Technologies in Health (CADTH) review of nirsevimab. T.P. received grants from GSK. M.R. is a national coordinator and/or principal investigator for several clinical trials sponsored by GSK and other vaccine manufacturers and received grants from GSK to his institution. J.A.E. received research support to her institution from AstraZeneca, GSK, Merck, and Pfizer, and is a consultant for AstraZeneca, AbbVie, Shanghai Ark Biopharmaceutical Co., GSK, Pfizer, Sanofi Pasteur, and Shionogi. N.P.K. received research support to her institution from GSK, and grants/contracts to her institution from Pfizer, Sanofi Pasteur, Merck, and CSL Seqirus. M.P.R. received support from Demedica. SKS received funding from GSK for attending conferences. Other authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Determinants of maternal-fetal cytomegalovirus (CMV) transmission and factors influencing the severity of congenital CMV (cCMV) infection are not well understood., Methods: We conducted a descriptive, multi-center study in pregnant women ≥18 years old with primary CMV infection and their newborns (NCT01251744) to explore maternal immune responses to CMV and determine potential immunologic/virologic correlates of cCMV following primary infection during pregnancy. We developed alternative approaches looking into univariate/multivariate factors associated with cCMV, including a participant clustering/stratification approach and an interpretable predictive model-based approach using trained decision trees for risk prediction (post-hoc analyses)., Results: Pregnant women were grouped in three distinct clusters with similar baseline characteristics, particularly gestational age at diagnosis. We observed a trend for higher viral loads in urine and saliva samples from mothers of infants with cCMV versus without cCMV. When using a trained predictive-model approach that accounts for interaction effects between variables, anti-pentamer IgG antibody concentration and viral load in saliva were identified as biomarkers jointly associated with the risk of maternal-fetal CMV transmission., Conclusion: We identified biomarkers of CMV maternal-fetal transmission. After validation in larger studies, our findings will guide the management of primary infection during pregnancy and the development of vaccines against cCMV., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed., Methods: We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed., Results: The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed., Conclusions: The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT04605159.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants. This phase 1/2, observer-blind, randomized, controlled study assessed the safety and immunogenicity of an investigational chimpanzee-derived adenoviral vector RSV vaccine (ChAd155-RSV, expressing RSV F, N, and M2-1) in infants., Methods: Healthy 6- to 7-month-olds were 1:1:1-randomized to receive 1 low ChAd155-RSV dose (1.5 × 1010 viral particles) followed by placebo (RSV&#95;1D); 2 high ChAd155-RSV doses (5 × 1010 viral particles) (RSV&#95;2D); or active comparator vaccines/placebo (comparator) on days 1 and 31. Follow-up lasted approximately 2 years., Results: Two hundred one infants were vaccinated (RSV&#95;1D: 65; RSV&#95;2D: 71; comparator: 65); 159 were RSV-seronaive at baseline. Most solicited and unsolicited adverse events after ChAd155-RSV occurred at similar or lower rates than after active comparators. In infants who developed RSV infection, there was no evidence of vaccine-associated enhanced respiratory disease (VAERD). RSV-A neutralizing titers and RSV F-binding antibody concentrations were higher post-ChAd155-RSV than postcomparator at days 31, 61, and end of RSV season 1 (mean follow-up, 7 months). High-dose ChAd155-RSV induced stronger responses than low-dose, with further increases post-dose 2., Conclusions: ChAd155-RSV administered to 6- to 7-month-olds had a reactogenicity/safety profile like other childhood vaccines, showed no evidence of VAERD, and induced a humoral immune response. Clinical Trials Registration. NCT03636906., Competing Interests: Potential conflicts of interest. V. N., Y. Z., W. P., D. F., I. D., A. G. L., R. M., S. K. S., and N. V. are or were employees of GSK during the conduct of the study. I. D., W. P., and S. K. S. hold GSK shares/stocks. R. M. and S. K. S. hold stock/stock options in Moderna. B. T., E. J. A., B. S. C., E. C. D., H. S., J. D. C., J. M. M. A., K. L., M. M. M.-P., M. R., S. N. F., F. B.-A., and T. P. report grants and/or other support from GSK for the conduct of the study. J. M. L. reports grants from GSK paid to her institution for the conduct of the study and holds the CIHR-GSK Chair in Pediatric Vaccinology at Dalhousie University. B. T. reports grants from GSK, Merck, and Pfizer for other trials. C. e. reports support for scientific meetings from GSK and ViiV and advisory consultancy fees from GSK. E. J. A. has consulted for Pfizer, Sanofi Pasteur, GSK, Janssen, Moderna, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Novavax, Sanofi Pasteur, Janssen, and Micron; he serves on a safety monitoring board for Kentucky BioProcessing and Sanofi Pasteur; serves on a data adjudication board for WCG and ACI Clinical; and his institution has also received funding from the National Institutes of Health to conduct clinical trials of COVID-19 vaccines. B. S. C. reports grants for other vaccine trials from GSK and MSD paid to his institution. E. C. D. performs contract work for the Eskisehir Osmangazi University funded by GSK, Sanofi Pasteur, and Pfizer. E. K. reports honoraria for lectures from GSK, MSD, AstraZeneca, Sanofi, and Pfizer. E. L.-M. reports grants from Centro de Estudios en Infectología Pediátrica. F. M.-T. reports grants from Janssen, MSD, and AstraZeneca; personal fees from Ablynx, GSK, Pfizer, MSD, Sanofi Pasteur, Novavax, Seqirus, and Biofabri; nonfinancial support from GSK, Pfizer, MSD, and Seqirus; and trial fees paid to his institution from these different companies (except Biofabri). H. S. reports personal fees and trial fees paid to his institution from MSD, Seqirus, Pfizer, Janssen, and Sanofi Pasteur. I. S. C. has received payment to his institution from GSK for the conduct of the study, by contract approved by the corresponding ethical committees and health authorities, and for trials of other vaccine manufacturers, and has received grants and/or honoraria as a consultant/advisor/speaker or for attending conferences and practical courses from GSK and other vaccine manufacturers. J. D. C. is a member of the Committee on Infectious Diseases of the American Academy of Pediatrics and reports funds paid to his university to study RSV vaccines. J. D.-D. reports grants from GSK, MSD, and Sanofi Pasteur paid to his institution. J. M. M. A. reports fees for medical meetings from GSK and Pfizer. K. L. reports grants from ReViral and Shionogi. M. M.-P. reports grants from MSD, Roche, GSK, Janssen, Takeda, and Syneos. M. R. reports grants for other vaccine trials from GSK and other vaccine manufacturers paid to his institution. S. N. F. reports fees paid to his institution for attending meetings, advisory boards, and/or grants for clinical trials from AstraZeneca/Medimmune, GSK, J&J, Pfizer, Sanofi, Seqirus, Sandoz, Valneva, Novavax, and Merck. X. S.-L. reports grants from Cevaxin Vaccine Research Center. F. B.-A. reports consultancy fees from GSK, Pfizer, and MSD and grants from MSD. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Developing a vaccine to prevent congenital cytomegalovirus (CMV) infection and newborn disability requires an understanding of infection incidence. In a prospective cohort study of 363 adolescent girls (NCT01691820), CMV serostatus, primary infection, and secondary infection were determined in blood and urine samples collected at enrollment and every 4 months for 3 years. Baseline CMV seroprevalence was 58%. Primary infection occurred in 14.8% of seronegative girls. Among seropositive girls, 5.9% had ≥4-fold increase in anti-CMV antibody, and 23.9% shed CMV DNA in urine. Our findings provide insights on infection epidemiology and highlight the need for more standardized markers of secondary infection., Competing Interests: Potential conflicts of interest. M. D., N. D. S., A. G., A. A. P., F. R., J. Y., and I. D. are employed by and hold shares of GSK. J.-M. D. and L. G. are employees of GSK. R. P. was an employee of GSK at the time of the study; he holds shares of GSK, is currently an employee of Moderna Inc, and holds shares of Moderna Inc. D. A. and S. B. received a grant from GSK for this study. S. B. is a member of advisory committees for Merck, Moderna Therapeutics, and Sanofi, and received grants from Pfizer and Moderna outside the submitted work. E. M. Y. reports no potential conflicts. The authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: In a phase 1/2 study, a maternal respiratory syncytial virus vaccine candidate (RSVPreF3) demonstrated an acceptable safety profile and efficiently increased RSV-specific humoral immune responses in non-pregnant women., Methods: In this phase 2 observer-blind, placebo-controlled, randomized clinical trial (NCT04126213), the safety of RSVPreF3 (60 or 120 µg), administered during late second or third trimester, was evaluated in 213 18- to 40-year-old healthy pregnant women through 6 months postdelivery and their offspring through infancy; immunogenicity was evaluated through day 43 postdelivery and day 181 postbirth, respectively., Results: RSVPreF3 was well tolerated. No pregnancy-related or neonatal adverse events of special interest were considered vaccine/placebo related. In the 60 and 120 µg RSVPreF3 groups: (1) neutralizing antibody (nAb) titers in mothers increased 12.7- and 14.9-fold against RSV-A and 10.6- and 13.2-fold against RSV-B, respectively, 1 month postvaccination and remained 8.9-10.0-fold over prevaccination at day 43 postdelivery; (2) nAb titers were consistently higher compared to placebo recipients; (3) placental transfer ratios for anti-RSVPreF3 antibodies at birth were 1.62 and 1.90, respectively, and (4) nAb levels in infants were highest at birth and declined through day 181 postbirth., Conclusions: RSVPreF3 maternal vaccination had an acceptable safety risk profile and induced robust RSV-specific immune responses with successful antibody transfer to their newborns., Clinical Trials Registration: NCT04126213., Competing Interests: Potential conflicts of interest. A. N. T., H. Q., I. D., M. H., M. d. H., O. H., P. L., M. M. C., and Z. B. are or were employees of the GSK group of companies at the time of the study. A. N. T., I. D., M. d. H., M. M. C., and O. H. report holding shares of the GSK group of companies. P. L. reports personal fees from GSK. O. R. declares personal fees from CEVAXIN during the conduct of the study and outside the submitted work. A. K. declares institutional financial support from GSK for conducting this study; investigator-initiated grants from Valneva and Pfizer, the latter two outside this study; and declares no personal fees from any vaccine companies. M. G. S. declares personal fees and institutional financial support from GSK during the conduct of the study. J. M. L. declares holding the Canadian Institutes of Health Research-GSK Chair in Pediatric Vaccinology at Dalhousie University; institutional financial support from GSK during the conduct of the study; other compensation from Immunovaccine; and grants from Novavax, Janssen, and Regeneron, outside the submitted work; in all cases these are paid to Dalhousie University. J. B. declares institutional financial support from GSK, Pfizer, and MedImmune during the conduct of the study and outside the submitted work. S. A. M. has received institution grants and personal fees from BMGF and GSK; and institution grants from Pfizer, Novavax, AstraZeneca, and Minervax during the conduct of the study. R. G. declares personal fees from Optimal Clinical Trials during the conduct of the study. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015)., Methods: In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen's κ statistics., Results: Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95-1.00), but less concordant for severe RSV-LRTI (κ: 0.47-0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs., Conclusions: Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI., Clinical Trial Registration: NCT01995175., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

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., Competing Interests: Potential conflicts of interest. J. D. D. reports personal fees/grants from GSK, Sanofi Pasteur and MSD and nonfinancial support from Sanofi Pasteur and MSD. X. S. L. reports grants from Cevaxin. Outside the submitted work, C. E. reports support from GSK and ViiV for scientific congress attendance. F. M. T. reports personal fees and nonfinancial support from GSK, Medimmune, Pfizer, MSD, Sanofi Pasteur, Astra Zeneca, and Seqirus. J. M. L. reports grants from GSK and Janssen, personal fees from Pfizer, and nonfinancial support from Immunovaccine. J. B. D. reports consulting fees from Sanofi Pasteur. S. E. reports personal fees and grants from GSK, Sanofi, and Vifor and grants from Abbott and Pfizer. P. M., T. L. A. N., V. N., W. W., Y. Z., I. D., A. L., A. G. L., and N. V. are employees of the GSK group of companies or were employees during the conduct of the study. P. M., W. W., I. D., and A. L. hold shares in the GSK group of companies. The institutions of J. D. D., A. C., A. A. B., F. M. T., J. M. L., J. B. D., and S. E. received funds from GSK for conducting the present work. Outside the submitted work, the institution of F. M. T. received funds from GSK, Ablynx, Jansen, Regeneron, Pfizer, MSD, Novavax, Roche, Astra Zeneca and Seqirus, and the institution of J. B. D. received grants from Merck and Medimmune/Astra Zeneca. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Respiratory syncytial virus (RSV) infection causes a substantial lower-respiratory-tract disease burden in infants, constituting a global priority for vaccine development. We evaluated immunogenicity, safety and efficacy of a chimpanzee adenovirus (ChAd)-based vaccine candidate, ChAd155-RSV, in a bovine RSV (bRSV) challenge model. This model closely reproduces the pathogenesis/clinical manifestations of severe pediatric RSV disease. In seronegative calves, ChAd155-RSV elicits robust neutralizing antibody responses against human RSV. Two doses protect calves from clinical symptoms/lung pathological changes, and reduce nasal/lung virus loads after both a short (4-week) and a long (16-week) interval between last immunization and subsequent bRSV challenge. The one-dose regimen confers near-complete or significant protection after short-term or long-term intervals before challenge, respectively. The presence of pre-existing bRSV-antibodies does not affect short-term efficacy of the two-dose regimen. Immunized calves present no clinical signs of enhanced respiratory disease. Collectively, this supports the development of ChAd155-RSV as an RSV vaccine candidate for infants., (© 2022. The Author(s).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life., Methods: In this first-in-human, placebo-controlled study, 502 healthy nonpregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3) or placebo., Results: Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4%-53.2%) versus placebo (0%-15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with prevaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8- to 14-fold and 12- to 21-fold at day 8 and persisted 5- to 6-fold and 6- to 8-fold higher until day 91 in the RSVPreF3 groups versus 1-fold in placebo. Comparisons at day 8 and day 31 showed that the higher dose levels were significantly more immunogenic than the lowest one., Conclusions: The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women., Clinical Trials Registration: NCT03674177., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

A recombinant respiratory syncytial virus (RSV) fusion glycoprotein candidate vaccine (RSV-PreF) manufactured in Chinese hamster ovary cells was developed for immunization of pregnant women, to protect newborns against RSV disease through trans-placental antibody transfer. Traces of a host-cell protein, hamster neogenin (haNEO1), were identified in purified RSV-PreF antigen material. Given the high amino-acid sequence homology between haNEO1 and human neogenin (huNEO1), there was a risk that potential vaccine-induced anti-neogenin immunity could affect huNEO1 function in mother or fetus. Anti-huNEO1 IgGs were measured by enzyme-linked immunosorbent assay in sera from rabbits and trial participants (Phase 1 and 2 trials enrolling 128 men and 500 non-pregnant women, respectively; NCT01905215/NCT02360475) collected after immunization with RSV-PreF formulations containing different antigen doses with/without aluminum-hydroxide adjuvant. In rabbits, four injections administered at 14-day intervals induced huNEO1-specific IgG responses in an antigen-dose- and adjuvant-dependent manner, which plateaued in the highest-dose groups after three injections. In humans, no vaccination-induced anti-huNEO1 IgG responses were detected upon a single immunization, as the values in vaccine and control groups fluctuated around pre-vaccination levels up to 90/360 days post-vaccination. A minority of participants had anti-huNEO1 levels ≥ assay cutoff before vaccination, which did not increase post-vaccination. Thus, despite detecting vaccine-induced huNEO1-specific responses in rabbits, we found no evidence that the candidate vaccine had induced anti-huNEO1 immunity in human adults. The antigen purification process was nevertheless optimized, and haNEO1-reduced vaccines were used in a subsequent Phase 2 trial enrolling 400 non-pregnant women (NCT02956837), in which again no vaccine-induced anti-huNEO1 responses were detected.

Background: Respiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins., Methods: Healthy 18-45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies., Results: There were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A-neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F-specific interferon γ-secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose., Conclusions: In adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns., Clinical Trials Registration: NCT02491463., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV) is a common cause of respiratory tract illness and hospitalization in neonates and infants. RSV vaccination during pregnancy may protect offspring in their first months of life., Methods: This randomized, observer-blind, multicenter, phase 2 study evaluated the immunogenicity and safety of an RSV candidate vaccine in healthy nonpregnant women aged 18-45 years. Four hundred participants were randomized (1:1:1:1) to receive a single intramuscular dose of vaccine containing 30 µg, 60 µg, or 120 µg of RSV fusion protein engineered to preferentially maintain a prefusion conformation (RSV-PreF vaccine) or placebo., Results: Thirty days postvaccination, RSV-A neutralizing antibody geometric mean titers (GMTs) increased 3.75-, 4.42- and 4.36-fold; RSV-B neutralizing antibody GMTs 2.36-, 2.54- and 2.76-fold; and palivizumab competing antibody (PCA) concentrations 11.69-, 14.38- and 14.24-fold compared with baseline levels in the 30 µg, 60 µg, and 120 µg RSV-PreF groups, respectively. Antibody titers and PCA concentrations at day 30 were significantly higher with the 120 µg compared to the 30 µg RSV-PreF vaccine. All RSV-PreF vaccine formulations and the placebo had similar reactogenicity profiles. No serious adverse events were considered to be related to the RSV-PreF vaccine., Conclusions: The 3 formulations of the investigational RSV-PreF vaccine were well-tolerated and induced RSV-A and RSV-B neutralizing antibodies and PCAs in healthy, nonpregnant women., Clinical Trials Registration: NCT02956837., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Pregnancy and the postpartum period are associated with elevated risks to both mother and infant from infectious disease. Vaccination of pregnant women, also called maternal immunization, has the potential to protect pregnant women, foetuses and infants from several vaccine-preventable diseases. Maternal immunoglobulin G antibodies are actively transferred through the placenta to provide passive immunity to new-borns during the first months of life, until the time for infant vaccinations or until the period of greatest susceptibility has passed. Currently, inactivated influenza, tetanus, and pertussis vaccines are recommended during pregnancy in many countries, but other vaccines may also be administered to pregnant women when risk factors are present. Several new vaccines with a specific indication for use during pregnancy are under development (e.g. respiratory syncytial virus and group B streptococcus vaccines). Years of experience suggest that maternal immunization against influenza, tetanus or pertussis has an acceptable safety profile, is well tolerated, effective and confers significant benefits to pregnant women and their infants. This review describes the principles of maternal immunization and provides an update of the recent evidence regarding the use and timing of maternal immunization. Finally, the barriers preventing wider vaccination coverage and the current limitations in addressing these are also described ( Supplementary Material ). Key messages Maternal immunization gives pregnant women greater protection against infectious diseases; induces high levels of maternal antibodies that can be transferred to the foetus; and helps protect new-borns during their first months of life, until they are old enough to be vaccinated. Pregnant women and new-borns are more vulnerable to infectious diseases than the overall population; nevertheless, vaccination rates are often low in pregnant women. This review provides an update of the recent evidence regarding the use and timing of maternal immunization and describes the barriers preventing wider vaccination uptake and the current limitations in addressing these.

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.

To investigate long-term antibody persistence following the administration of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV), we present results of 2 follow-up studies assessing antibody persistence following 2 3+1 schedules up to 4 (NCT00624819 - Study A) and 5 years (NCT00891176 - Study B) post-booster vaccination. In Study A, antibody persistence was measured one, 2 and 4 years post-booster in children previously primed and boosted with PHiD-CV, or primed with the 7-valent pneumococcal conjugate vaccine (7vCRM) and boosted with either PHiD-CV or 7vCRM. In Study B, PHiD-CV was co-administered with meningococcal vaccines, and pneumococcal antibody persistence was measured 2, 3 and 5 years post-booster. An age-matched control group, unvaccinated against Streptococcus pneumoniae, was enrolled in Study A, allowing assessment of immunologic memory by administration of one dose of PHiD-CV to both primed (4 years post-booster) and unprimed 6-year-old children. Four years post-booster (Study A), antibody concentrations and opsonophagocytic activity (OPA) titers remained higher compared to the pre-booster timepoint, with no major differences between the 3 primed groups. Antibody persistence was also observed in Study B, with minimal differences between groups. The additional PHiD-CV dose administered 4 years post-booster in Study A elicited more robust immune responses in primed children than in unprimed children. Long-term serotype-specific antibody persistence and robust immunologic memory responses observed in these 2 studies suggest induction of long-term protection against pneumococcal disease after PHiD-CV vaccination.

Background:  Respiratory syncytial virus (RSV) is a leading cause of childhood bronchiolitis and pneumonia, particularly in early infancy. Immunization of pregnant women could boost preexisting immune responses, providing passive protection to newborns through placental transfer of anti-RSV antibody., Methods:  In this first-in-humans clinical trial of a purified recombinant RSV protein F vaccine engineered to preferentially maintain prefusion conformation (RSV-PreF), 128 healthy men 18-44 years old were randomized to one dose of a RSV-PreF vaccine containing 10, 30, or 60 µg of RSV-PreF antigen, with or without alum adjuvant, or control, and followed for one year for safety and immunogenicity outcomes., Results:  Injection site pain was the most common adverse event, reported by up to 81.3% of participants. The highest RSV neutralizing antibody responses were in the 30 µg RSV-PreF/alum, 60 µg RSV-PreF/alum, and 60 µg RSV-PreF/nonadjuvant groups. Responses were evident on day 7, and 30 days after vaccination these participants had RSV-A neutralizing antibody titers of ≥1:512, and >70% had titers of 1:1024, with titers increasing by 3.2-4.9 fold. Responses remained high on day 60 but waned on days 180 and 360., Conclusions:  The RSV-PreF vaccine elicited rapid RSV neutralizing antibody responses in healthy young men, with an acceptable adverse event profile., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: During the influenza pandemic 2009-2010, an AS03-adjuvanted A(H1N1)pdm09 vaccine was used extensively in children 6 months of age and older, and during the 2010-2011 influenza season, the A(H1N1)pdm09 strain was included in the seasonal trivalent inactivated influenza vaccine (TIV) without adjuvant. We evaluated the immunogenicity and safety of TIV in children previously vaccinated with the AS03-adjuvanted A(H1N1)pdm09 vaccine., Methods: Healthy children were randomized (1:1) to receive TIV or a control vaccine. Children were aged 6 months to 9 years (n = 154) and adolescents 10-17 years (n = 77) when they received AS03-adjuvanted A(H1N1)pdm09 vaccine at least 6 months before study enrolment. Hemagglutination inhibition (HI) and neutralizing antibody responses against the A(H1N1)pdm09 strain were evaluated before (day 0) and at day 28 and month 6 after study vaccination. Reactogenicity was assessed during the 7 day postvaccination period, and safety was assessed for 6 months., Results: At day 0, >93.9% of all children had HI titers ≥1:40 for the A(H1N1)pdm09 strain, which increased to 100% at both day 28 and month 6 in the TIV group. Between days 0 and 28, HI antibody geometric mean titers against A(H1N1)pdm09 increased by 9-fold and 4-fold in children 6 months to 9 years of age and 10-17 years of age, respectively., Conclusion: AS03-adjuvanted A(H1N1)pdm09 vaccine-induced robust immune responses in children that persisted into the next season, yet were still boosted by TIV containing A(H1N1)pdm09. The reactogenicity and safety profile of TIV did not appear compromised by prior receipt of AS03-adjuvanted A(H1N1)pdm09 vaccine.

We present an age-structured dynamic transmission model for cytomegalovirus (CMV) in the United States, based on natural history and available data, primarily aiming to combine the available qualitative and quantitative knowledge toward more complex modeling frameworks to better reflect the underlying biology and epidemiology of the CMV infection. The model structure explicitly accounts for primary infections, reactivations and re-infections. Duration of infectiousness and likelihood of reactivation were both assumed to be age-dependent, and natural reduction in the re-infection risk following primary infection was included. We used an empirical social contact matrix (POLYMOD-based) as support for CMV transmission between different age groups. The baseline model reproduced well the age-stratified seroprevalence data (National Health and Nutrition Examination Survey III) used for calibration. The model was further used to explore the potential impact of hypothetical vaccination on reducing congenital CMV infection under various vaccine profiles and vaccination scenarios. Our preliminary model-based simulations suggested that while infant vaccination may represent an attractive way to reduce congenital CMV infection over time, adolescent female vaccination with an adequate routine booster platform may, under certain conditions, provide an alternative. However, for such tools to be considered toward actual decision-making, enhanced validations based on additional studies and data would be further necessary. The modeling framework presented in this paper was designed to be sufficiently general and flexible, such that it can allow for further adaptations to reflect new knowledge or data that may become available in the future.

In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.

Background: Induction of immunologic memory was assessed following primary vaccination with 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV)., Methods: Infants were randomized (1:1) to receive 3 doses of PHiD-CV or 7vCRM (7-valent CRM197-conjugated pneumococcal conjugate vaccine [PCV]) at 2, 3, and 4 months of age followed by 23-valent pneumococcal polysaccharide vaccine (23vPS) booster dose at 11 to 14 months of age. Pneumococcal geometric mean antibody concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers were measured., Results: Postprimary immune responses were consistent with those in previous PHiD-CV and 7vCRM studies. Following 23vPS boosting, vaccine serotype-specific antibody GMCs increased 6.5- to 33.3-fold and 4.8- to 32.2-fold versus prebooster in the PHiD-CV and 7vCRM groups, respectively. Postbooster OPA titers increased 2.8- to 38.8-fold and 2.6- to 58.9-fold, respectively. Postbooster antibody GMCs exceeded postprimary levels but, for some serotypes, postbooster OPA geometric mean titers were lower than postprimary in both groups. An additional dose of the same PCV received for priming was administered to 52 children aged 46 to 50 months, resulting in higher responses versus postprimary vaccination for all serotypes, but not always higher than post-23vPS booster., Conclusions: Induction of immunologic memory following PHiD-CV priming was confirmed. Additional PCV boosting in 4-year-olds did not provide strong evidence of hyporesponsiveness induced by previous 23vPS boosting. However, our results did not rule out depletion of the memory B cell pool following 23vPS vaccination, resulting in subsequent attenuated immune responses, and therefore support the use of PCV rather than 23vPS for booster vaccination in the second year of life.

Background: We evaluated catch-up vaccination schedules with 10-valent pneumococcal nontypeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV)., Methods: In this open, controlled study, children stratified into 4 age groups (N = 150 each) were vaccinated with PHiD-CV: (a) <6 months reference group: 3 primary doses with booster at 12 to 15 months, (b) 7 to 11 months: 2 doses and booster at 12 to 15 months, (c) 12 to 23 months: 2 doses, and (d) 2 to 5 years: 1 dose. Serotype-specific pneumococcal responses were measured by 22F-inhibition enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic activity (OPA) assay., Results: In the 7 to 11 months group postbooster antibody geometric mean concentrations (except for 2 serotypes) and OPA geometric mean titers (GMTs) were in the same ranges or higher relative to postbooster values in the <6 months reference group. Following 2 doses in the 12 to 23 months group, the percentages reaching threshold levels for ELISA (except for serotypes 6B and 23F) and OPA (except for serotype 1) were comparable or higher than <6 months reference postbooster values. Antibody geometric mean concentrations and OPA GMTs, while comparable or higher than reference postprimary values, were for some serotypes lower than reference postbooster values. Following 1 dose in the 2 to 5 years group ELISA responses were lower than the reference group for several serotypes., Conclusions: A catch-up PHiD-CV schedule of 2 doses and booster for children 7 to 11 months of age was acceptable. For children 12 to 23 months of age, 2 doses seem to provide adequate priming although a booster dose might confer further benefit. Responses following 1 dose in children 2 to 5 years of age suggest that 2 doses may be preferable.

The safety and reactogenicity profiles of the 10-valent pneumococcal conjugate vaccine, PHiD-CV, and 7vCRM were comparable within the Philippines and Poland when coadministered as a booster dose with DTPw-HBV/Hib and poliovirus vaccines to toddlers primed with the same vaccines. Robust immune responses for all 10 vaccine pneumococcal serotypes and protein D following PHiD-CV booster vaccination were indicative of effective priming.

We report on the evaluation of the immunogenicity and reactogenicity/safety of AS03-adjuvanted vaccine against pandemic influenza A/H1N1/2009 in young children. In this open-label, randomized study, 157 healthy children aged 6-35 months received two doses (21 days apart) of split-virion inactivated A/California/7/2009 H1N1 vaccine containing either (i) 1.9microg hemagglutinin (HA) and AS03(B) (5.93mg tocopherol) (N=104) or (ii) 3.75mug HA and AS03(A) (11.86mg tocopherol) (N=53). At 21 days following the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the percentage of children with hemagglutination-inhibition titers of >or=40 against the vaccine strain rose from 3.0% before vaccination to 100%. The seroconversion rate was 99% and the geometric mean titer (GMT) increased from 6 to 313. After the second dose the GMT increased further to 2008. The higher dose AS03(A)-adjuvanted 3.75microg HA vaccine did not further increase the immune response. Solicited symptoms reported within 7 days following vaccination were mainly mild to moderate. After the first dose of AS03(B)-adjuvanted vaccine (1.9microg HA) the most common solicited symptoms were pain at the injection site (35.6%) and irritability (31.7%). Fever (axillary >or=37.5 degrees C) was reported with an incidence of 20.2%. After the second dose reactogenicity tended to increase (injection site pain: 41.3%; irritability: 46.2%; fever >or=37.5 degrees C: 67.3%). Spontaneously reported adverse events with an intensity that prevented normal activities were documented for 2.9-6.7% of doses with only one event (vomiting) considered related to vaccination. There was one serious adverse event reported in the AS03(A)-adjuvanted 3.75microg HA vaccine group (traumatic brain injury) which was not considered as related to vaccination. In conclusion, these data suggest that a first dose of AS03(B)-adjuvanted A/H1N1/2009 vaccine containing 1.9microg HA in children 6-35 months old is highly immunogenic and that the overall reactogenicity profile is acceptable although reactions including fever tend to increase after a second dose.

Background: A booster dose of pneumococcal conjugate vaccine may be administered at the same age as measles-mumps-rubella-varicella (MMRV) vaccination. This study examined the safety, reactogenicity, and immunogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) when coadministered with MMRV vaccine., Methods: In this open, controlled study, 325 healthy children aged 12 to 14 months were randomized to 1 of 3 groups: the first group (N = 110) received PHiD-CV and MMRV vaccine followed 6 to 8 weeks later by MMRV and DTPa-HBV-IPV/Hib vaccines; the second group (N = 101) received DTPa-HBV-IPV/Hib and MMRV vaccines followed 6 to 8 weeks later by PHiD-CV and MMRV vaccine; the third group (N = 114) received PHiD-CV and DTPa-HBV-IPV/Hib vaccine during 1 vaccination visit. Immune responses were assessed with GlaxoSmithKline's 22F-inhibition enzyme-linked immunosorbent assay (for PHiD-CV), commercial enzyme-linked immunosorbent assay (for MMR), or indirect immunofluorescence assay (for varicella). Adverse events were recorded by the parents/guardians., Results: After the first vaccination, 2 peaks in fever (rectal temperature > or =38 degrees C) were observed; at days 0 to 2, related to PHiD-CV and DTPa-HBV-IPV/Hib vaccination, and at days 4 to 12, related to MMRV vaccination. Booster responses to pneumococcal antigens and protein D and seroconversion rates for all MMRV vaccine components were high., Conclusions: PHiD-CV and MMRV vaccine can be coadministered without compromising the safety and immunogenicity profiles of either vaccine.

Background: Immunogenicity of the candidate 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed when coadministered with other routine pediatric vaccines including different Neisseria meningitidis serogroup C conjugate vaccines., Methods: One thousand five hundred forty-eight healthy infants received, according to a balanced (1:1:1:1) randomization, either PHiD-CV coadministered with (1) DTPa-HBV-IPV/Hib (Infanrix hexa) and MenC-CRM (Meningitec), (2) DTPa-HBV-IPV/Hib and MenC-TT (NeisVac-C), or (3) DTPa-HBV-IPV (Infanrix penta/Pediarix) and Hib-MenC-TT (Menitorix); or 7vCRM (Prevenar/Prevnar) coadministered with DTPa-HBV-IPV and Hib-MenC-TT at 2-4-6 months of age with a booster dose at 11-18 months. Serotype-specific pneumococcal responses were measured by 22F-inhibition ELISA and opsonophagocytic (OPA) assay., Results: In all 3 coadministration groups, PHiD-CV was immunogenic for each of the 10 pneumococcal vaccine serotypes as assessed by post-primary and post-booster antibody ELISA and OPA responses. When coadministered with DTPa-HBV-IPV, Hib, and MenC antigens, PHiD-CV responses after the third primary dose were within the same range as 7vCRM responses in terms of the percentage of subjects achieving an ELISA antibody concentration >or=0.2 microg/mL for all common vaccine serotypes (over 92% of subjects) except for serotype 6B (at least 87% of subjects). ELISA and OPA immune responses were also evident after the second primary doses of PHiD-CV or 7vCRM vaccine, although antibody levels were below that achieved after 3 primary doses, particularly for serotypes 6B and 23F. The kinetics of the immune responses from after the second dose to after the booster dose were similar for most of the serotypes in both PHiD-CV and 7vCRM groups., Conclusions: PHiD-CV was immunogenic when coadministered with other routine pediatric vaccines including MenC conjugate vaccines.

Background: Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was evaluated when coadministered with DTPw-HBV/Hib and OPV at 6, 10, and 14 weeks of age in the Philippines, or with DTPw-HBV/Hib and IPV at 2, 4, and 6 months of age in Poland., Methods: In this double-blind, controlled study (107007/NCT00344318), 400 Filipino and 406 Polish infants 6 to 12 weeks of age were randomized (3:1) to receive either PHiD-CV or the 7-valent pneumococcal conjugate vaccine (7vCRM). Immune responses were assessed 1 month post-dose III., Results: Percentages of infants with anti-pneumococcal antibody concentrations >or=0.2 microg/mL (GSK's 22F-inhibition ELISA) were within the same range for both pneumococcal conjugate vaccine groups, with the exception of serotypes 6B and 23F for which lower percentages were observed in the PHiD-CV group in Poland. At least 98.2% of PHiD-CV vaccinees had antibody concentrations >or=0.2 microg/mL against pneumococcal serotypes 1, 5, and 7F. In both countries, anti-pneumococcal antibody geometric mean concentrations against serotypes 18C and 19F were higher in the PHiD-CV group than in the 7vCRM group. Antibody geometric mean concentrations for most of the other common serotypes were within the same range for both groups in the Philippines and were lower in the PHiD-CV group in Poland. Functional responses (opsonophagocytic activity [OPA]) were observed for all vaccine serotypes in both countries., Conclusions: PHiD-CV was immunogenic against each of the 10 pneumococcal vaccine serotypes when coadministered with DTPw-HBV/Hib and poliovirus vaccines.

Background: The choice of non-typeable Haemophilus influenzae Protein D as main carrier protein in the candidate 10-valent pneumococcal conjugate vaccine (PHiD-CV, GlaxoSmithKline Biologicals), was driven in part to avoid carrier-mediated suppression and possible bystander interference with coadministered vaccines. Immunogenicity data from 3 primary and 2 booster vaccination studies were assessed for possible impacts of PHiD-CV coadministration on immune responses to routinely administered childhood vaccines, in comparison to 7-valent pneumococcal conjugate vaccine (7vCRM) coadministration., Methods: Randomized, controlled studies in which PHiD-CV or 7vCRM vaccines were coadministered with DTPa-[HBV]-IPV/Hib, DTPa-[HBV]-IPV, DTPw-HBV/Hib, IPV, and OPV, combined Hib-Neisseria meningitidis serogroup C vaccine (Hib-MenC-TT), standalone MenC-TT or MenC-CRM vaccines., Results: One month after primary vaccination, >96% of PHiD-CV recipients had seroprotective antibody concentrations against diphtheria, tetanus, poliovirus types 1 and 3, Hib (>or=0.15 microg/mL), SBA-MenC (>or=1:8), and >94% were seropositive for antibodies against pertussis antigens. Somewhat lower responses against poliovirus type 2 in study A (compared with poliovirus type 1 and 2 responses) and hepatitis B in the 6-, 10-, and 14-week schedule in the Philippines (compared with hepatitis B responses in the other studies) were observed after coadministration of both PHiD-CV and 7vCRM vaccines. Antitetanus and anti-PRP antibody geometric mean concentrations (GMCs) tended to be higher after PHiD-CV coadministration, probably because of the TT carrier protein for serotype 18C in PHiD-CV. Booster vaccination induced substantial increases in antibody GMCs for all coadministered antigens. These responses were generally within the same range in PHiD-CV and 7vCRM groups. Observed anti-PRP responses remained higher in PHiD-CV recipients after the booster dose., Conclusions: Coadministration of PHiD-CV with commonly used childhood vaccines induced high levels of seroprotection/seropositivity against all targeted diseases. No evidence of negative interference on the immune response to any of the coadministered vaccine antigens was observed when compared with the current routine practice of 7vCRM coadministration.

Background: The immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was assessed and compared with the 7-valent pneumococcal conjugate vaccine (7vCRM)., Methods: Healthy subjects (1650) were randomized to be vaccinated with 3 doses of PHiD-CV or 7vCRM (Prevenar/Prevnar) at 2-3-4 months of age and a fourth booster dose at 12-18 months. Serotype-specific pneumococcal responses (GlaxoSmithKline's ELISA with 22F-inhibition) and opsonophagocytic activity (OPA) were measured 1 month after primary and booster vaccinations., Results: The primary objective to demonstrate noninferiority of PHiD-CV versus 7vCRM (in terms of percentage of subjects with antibody concentration >or=0.2 microg/mL) for at least 7 of the 10 vaccine serotypes was reached as noninferiority was demonstrated for 8 serotypes. Although, noninferiority could not be demonstrated for ELISA responses against serotypes 6B and 23F, a post-hoc analysis of the percentage of subjects with OPA titers >or=8 suggested noninferiority for the 7 serotypes common to both vaccines including 6B and 23F.Priming of the immune system against all vaccine serotypes was confirmed by robust increases in ELISA antibody levels ( approximately 6.0-17 fold) and OPA titers ( approximately 8-93 fold) after a fourth consecutive dose of PHiD-CV., Conclusions: PHiD-CV induces ELISA and functional OPA antibodies for all vaccine serotypes after primary vaccination and is noninferior to 7vCRM in terms of ELISA and/or OPA threshold responses. Effective priming is further indicated by robust booster responses.

Primary vaccination with pneumococcal protein D conjugate vaccine in the first year of life induced clear ELISA and OPA responses, which varied considerably for the different serotypes. Antibody levels declined following primary vaccination but were restored (except for serotype 3) to above post-primary levels by booster vaccination in the second year of life. Antibody levels declined when measured in the fourth year of life, although remaining higher than in the non-immunized children. For some serotypes, antibody levels did not decline indicating exposure to pneumococci or cross-reacting bacteria. Development of natural immunity to several serotypes was evident from the increase in opsonophagocytic activity in the control group between booster and plain polysaccharide vaccination. Vigorous and rapid OPA and ELISA responses were elicited to all vaccine serotypes including serotype 3 following administration of plain polysaccharide vaccine in both the conjugate and control groups, being higher in the conjugate group (Study ID: 104083/NCT00169507).

Twinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is the first combined vaccine to provide protection against both hepatitis A and B. This review presents a critical analysis of antibody responses stratified by age following vaccination with Twinrix in 264 adults aged above 40 years. A month after completion of a 0-, 1-, 6-month vaccination schedule with Twinrix, a good response was observed for both anti-HAV and anti-HBs serum antibodies, suggesting that is an effective vaccine in older adults.