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Mohamed Khalil,1 Esam Azhar,2,3 Moujahed Kao,3 Noura Al-Kaiedi,3 Hatim Alhani,4 Ibrahim Al Olayan,5 Robert Pawinski,6,7 Kusuma Gopala,8 Walid Kandeil,7 Sameh Anis,7,9 Leen Jan Van Doorn,10 Rodrigo DeAntonio7 1Public Health and Research Development, Ministry of Health, Riyadh, Saudi Arabia; 2Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, 3Special Infectious Agents Unit, Bio-Safety Level 3, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 4Maternity and Children’s Hospital, Dammam, Saudi Arabia; 5Maternity and Children’s Hospital, Qassim, Saudi Arabia; 6Reckitt Benckiser Pharmaceuticals, Slough, UK; 7GlaxoSmithKline Vaccines, Wavre, Belgium; 8GlaxoSmithKline Pharmaceuticals Ltd, Bangalore, Karnataka, India; 9AbbVie Biopharmaceuticals GmbH, Dubai, United Arab Emirates; 10DDL Diagnostic Laboratory, Rijswijk, the Netherlands Purpose: Rotavirus (RV) is a leading cause of severe gastroenteritis (GE) in children across the world. As there is a lack of epidemiological data for RV gastroenteritis (RVGE) in Saudi Arabia, this hospital-based study was designed to estimate the disease burden of RVGE and assess the prevalent RV types in Saudi children younger than 5 years of age.Patients and methods: Children hospitalized for acute GE were enrolled at four pediatric referral hospitals in Saudi Arabia. The study was conducted from February 2007 to March 2008 and used the World Health Organization's generic protocol for RVGE surveillance. The Vesikari severity scale was used to assess the severity of RVGE. Stool samples were tested for RV using an enzyme-linked immunosorbent assay. Samples were further typed by reverse transcriptase–polymerase chain reaction and hybridization assay for determining the G and P types.Results: A total of 1,007 children were enrolled; the final analysis included 970 children, of whom 395 were RV positive, 568 were RV negative, and seven had unknown RV status. The proportion of RVGE among GE hospitalizations was 40.7% (95% confidence interval: 37.6–43.9). The highest percentage of RVGE hospitalizations (83.1%) was seen in children younger than 2 years of age. The highest proportion of RV among GE hospitalizations was in June 2007 with 57.1%. The most common RV types detected were G1P[8] (49.3%), G1G9P[8] (13.2%), and G9P[8] (9.6%). Before hospitalization, severe GE episodes occurred in 88.1% RV-positive and 79.6% RV-negative children. Overall, 94% children had recovered by the time they were discharged. Two children (one RV positive and one RV negative) died due to GE complications.Conclusion: RVGE is responsible for a high proportion of hospitalizations in Saudi children younger than 5 years of age. Routine RV vaccination has therefore been introduced into the national immunization program and may help reduce the morbidity, mortality, and disease burden associated with RVGE in Saudi Arabia. Keywords: disease burden, Saudi Arabia, rotavirus, RVGE, epidemiology

Muna Al Musawi,1 Hassan Zainaldeen,2 Fakrudeen Shafi,3 Sameh Anis,4 Rodrigo DeAntonio51Public Health Directorate, Ministry of Health, Manama, the Kingdom of Bahrain; 2Pediatric Department, Salmaniya Medical Complex, the Kingdom of Bahrain, Manama; 3GlaxoSmithKline Pharmaceuticals, Bangalore, India; 4GlaxoSmithKline Pharmaceuticals, Middle East and North Africa; 5GlaxoSmithKline Vaccines, Wavre, BelgiumPurpose: Rotavirus (RV) is the leading cause of morbidity and mortality in children under 5 years of age worldwide. This study assessed the role of RV as a cause of gastroenteritis (GE)-associated hospitalization in children, generating baseline information to evaluate the potential impact of the RV vaccine in reducing RVGE disease burden in the Kingdom of Bahrain.Methods: This single, pediatric hospital-based surveillance study was conducted over a period of 12 months beginning April 1, 2006. A total of 314 children aged under 5 years and hospitalized due to GE were enrolled in the study, following collection of written informed consent from parents/guardians. Stool samples were tested for the presence of RV using enzyme immunoassay, and a random subset of RV-positive samples was further genotyped using reverse transcriptase-polymerase chain reaction and reverse hybridization assay.Results: Of 314 enrolled children, 239 were included in the final analysis. RV was detected in 107 children (44.8%), mostly in the 6–23 months age group (82/107; 76.6%). RVGE occurred throughout the year, with the highest proportion occurring during April (26/42; 61.9%). G1P[8] was the most commonly detected RV strain (10/17; 58.8%) in the limited number of samples analyzed. Vomiting and severe RVGE were more commonly observed in RV-positive than RV-negative children before hospitalization (P = 0.0008 and 0.0204, respectively).Conclusion: In our study, RV accounted for over 40% of GE-associated hospitalizations and particularly affected children under 2 years of age. These data will serve as a baseline for assessing the potential changes in the epidemiology of RV disease and for evaluating the potential impact of the introduction of RV vaccination.Keywords: rotavirus, gastroenteritis, epidemiology, Kingdom of Bahrain

Abstract Background Non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae are major causes of bacterial acute otitis media (AOM). Data regarding AOM are limited in Latin America. This is the first active surveillance in a private setting in Venezuela to characterize the bacterial etiology of AOM in children < 5 years of age. Methods Between December 2008 and December 2009, 91 AOM episodes (including sporadic, recurrent and treatment failures) were studied in 87 children enrolled into a medical center in Caracas, Venezuela. Middle ear fluid samples were collected either by tympanocentesis or spontaneous otorrhea swab sampling method. Standard laboratory and microbiological techniques were used to identify bacteria and test for antimicrobial resistance. The results were interpreted according to Clinical Laboratory Standards Institute (CLSI) 2009 for non-meningitis isolates. All statistical analyses were performed using SAS 9.1 and Microsoft Excel (for graphical purposes). Results Overall, bacteria were cultured from 69.2% (63 of the 91 episodes); at least one pathogen (S. pneumoniae, H. influenzae, S. pyogenes or M. catarrhalis) was cultured from 65.9% (60/91) of episodes. H. influenzae (55.5%; 35/63 episodes) and S. pneumoniae (34.9%; 22/63 episodes) were the most frequently reported bacteria. Among H. influenzae isolates, 62.9% (22/35 episodes) were non-capsulated (NTHi) and 31.4% (11/35 episodes) were capsulated including types d, a, c and f, across all age groups. Low antibiotic resistance for H. influenzae was observed to amoxicillin/ampicillin (5.7%; 2/35 samples). NTHi was isolated in four of the six H. influenzae positive samples (66.7%) from recurrent episodes. Conclusions We found H. influenzae and S. pneumoniae to be the main pathogens causing AOM in Venezuela. Pneumococcal conjugate vaccines with efficacy against these bacterial pathogens may have the potential to maximize protection against AOM.

Abstract Background Acute otitis media (AOM) is one of the most frequently encountered bacterial infections in children aged < 5 years; Streptococcus pneumoniae (S. pneumoniae) and non-typeable Haemophilus influenzae (NTHi) are historically identified as primary AOM causes. Nevertheless, recent data on bacterial pathogens causing AOM in Latin America are limited. This prospective study aimed to identify and characterize bacterial etiology and serotypes of AOM cases including antimicrobial susceptibility in < 5 year old Colombian children. Methods From February 2008 to January 2009, children ≥3 months and < 5 years of age presenting with AOM and for whom a middle ear fluid (MEF) sample was available were enrolled in two medical centers in Cali, Colombia. MEF samples were collected either by tympanocentesis procedure or spontaneous otorrhea swab sampling. Bacteria were identified using standard laboratory methods, and antimicrobial resistance testing was performed based on the 2009 Clinical and Laboratory Standards Institute (CLSI) criteria. Most of the cases included in the study were sporadic in nature. Results Of the 106 enrolled children, 99 were included in the analysis. Bacteria were cultured from 62/99 (63%) of samples with S. pneumoniae, H. influenzae, or S. pyogenes. The most commonly isolated bacteria were H. influenzae in 31/99 (31%) and S. pneumoniae in 30/99 (30%) of samples. The majority of H. influenzae episodes were NTHi (27/31; 87%). 19F was the most frequently isolated pneumococcal serotype (10/30; 33%). Of the 30 S. pneumoniae positive samples, 8/30 (27%) were resistant to tetracycline, 5/30 (17%) to erythromycin and 8/30 (27%) had intermediate resistance to penicillin. All H. influenzae isolates tested were negative to beta-lactamase. Conclusions NTHi and S. pneumoniae are the leading causes of AOM in Colombian children. A pneumococcal conjugate vaccine that prevents both pathogens could be useful in maximizing protection against AOM.

The COVID-19 pandemic highlighted the critical role of viral genomic surveillance, prompting numerous countries to enhance their monitoring systems for acute respiratory infections (ARIs), especially influenza-like illnesses (ILIs). Given the significance of asymptomatic cases in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, cases often undetected by the ILI surveillance, a more comprehensive approach was essential to track the circulation of SARS-CoV-2 variants in the population. In response, many countries swiftly adopted wastewater surveillance, which allowed the early detection of SARS-CoV-2 variants before they were identified through molecular characterization from confirmed clinical cases. In this report, we detail the implementation of SARS-CoV-2 wastewater genomic surveillance in Panama during the first half of 2024. Wastewater samples were collected monthly in duplicate at two collection points from three districts of Panama city metropolitan area for testing by SARS-CoV-2 RT-qPCR, and positive samples were analyzed by next-generation sequencing to identify sublineages. A total of 36 wastewater samples and 822 samples obtained through the clinical surveillance were analyzed for molecular detection and sequencing. Sublineages detected by wastewater surveillance were compared to those detected by clinical surveillance for the same period of time. Wastewater surveillance allowed the identification of the Omicron sublineage JN.1.16.1 in the capital city and its surroundings, which was not detected by the clinical surveillance in the country, despite its global circulation. This highlights the critical need to sustain both genomic surveillance programs beyond the pandemic in countries like Panama that serve as pivotal exchange hubs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Gaitán, Zaldivar, Hernandez, Góndola, Chavarría, Moreno, Franco, DeAntonio, Mirazo, Cancela, Barnett, Martinez, Pascale and López-Vergès.)

As robust cellular responses are important for protection against dengue, this phase 2 study evaluated the kinetics and phenotype of T cell responses induced by TAK-003, a live-attenuated tetravalent dengue vaccine, in 4-16-year-old living in dengue-endemic countries (NCT02948829). Two hundred participants received TAK-003 on Days 1 and 90. Interferon-gamma (IFN-γ) enzyme-linked immunospot assay [ELISPOT] and intracellular cytokine staining were used to analyze T cell response and functionality, using peptide pools representing non-structural (NS) proteins NS3 and NS5 matching DENV-1, -2, -3, and -4 and DENV-2 NS1. One month after the second TAK-003 dose (Day 120), IFN-γ ELISPOT T cell response rates against any peptide pool were 97.1% (95% CI: 93.4% to 99.1%), and similar for baseline dengue seropositive (96.0%) and seronegative (98.6%) participants. IFN-γ ELISPOT T cell response rates at Day 120 were 79.8%, 90.2%, 77.3%, and 74.0%, against DENV-1, -2, -3, and -4, respectively, and remained elevated through 3 years post-vaccination. Multifunctional CD4 and CD8 T cell responses against DENV-2 NS peptides were observed, independent of baseline serostatus: CD8 T cells typically secreted IFN-γ and TNF-α whereas CD4 T cells secreted ≥ 2 of IFN-γ, IL-2 and TNF-α cytokines. NAb titers and seropositivity rates remained substantially elevated through 3 years post-vaccination. Overall, TAK-003 was well tolerated and elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in children and adolescents aged 4-16 years living in dengue-endemic countries. TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination., (© 2024. The Author(s).)

Introduction: Norovirus infection is a common cause of acute gastroenteritis (AGE). Surveillance activities are important to aid investigation into effective norovirus control strategies, including vaccination. Here, we report ancillary findings related to the incidence, prevalence, and etiology of AGE caused by norovirus in Panama after adjustment of study methodology to comply with national coronavirus disease 2019 (COVID-19) mandates., Methods: In January 2020, children aged <2 years began enrolling into an epidemiological study in Panama to estimate the burden of norovirus in preparation for evaluating upcoming prevention strategies. This included an observational, longitudinal, community-based AGE surveillance study and a hospital-based AGE surveillance study. For the longitudinal study, healthy children aged 5-18 months were enrolled from January 6 through March 23, 2020, with a follow-up of approximately 6 months. The last participant was contacted on September 23, 2020. For the hospital-based study, starting on January 21, 2020, children aged <2 years who were admitted to the Hospital del Niño Dr. José Renán Esquivel in Panama City due to AGE were evaluated. The last sample was collected on September 29, 2020. Collected stool samples were tested for norovirus as well as astrovirus, sapovirus, and various enteropathogens. Unfortunately, this study was disrupted by the subsequent implementation of disease transmission control procedures for the COVID-19 pandemic, and the study methodology was revised to comply with COVID-19 mandates., Results: In the longitudinal surveillance cohort [ N  = 400 (Chiriquí, n  = 239; Panama, n  = 161)], a total of 185 AGE episodes were documented (Chiriquí, n  = 85; Panama, n  = 100) resulting in an overall AGE incidence of 11.6 (95% CI: 9.99-13.4) episodes per 100 child-months. The norovirus-related AGE incidence was 0.3 (95% CI: 0.10-0.73) episodes per 100 child-months (5/185 AGE episodes) and the prevalence of norovirus was 4.6% (13/282 stool samples collected). In the hospital-based surveillance cohort, at least one pathogen was detected in 50% of samples (44/88 stool samples collected) and norovirus prevalence was 6.8% (6/88 stool samples collected)., Discussion: This report demonstrates how the occurrence of the COVID-19 pandemic hindered the conduct of clinical trials. However, this also created unique research opportunities to investigate the potential impact of pandemic control measures on the etiology of infectious diarrheal disease., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JW is a permanent employee of Takeda Vaccines. RD, MH-H, LA, ZC-B, LD, TL, XS, and BM received funding for the study from Takeda Vaccines to support the costs of the trial., (© 2024 DeAntonio, Hess-Holtz, Abrego, Capitan-Barrios, Donoso, De León, Sáez Llorens, Moreno and Weil.)

We conducted a dose-finding phase 2 study of the HilleVax bivalent virus-like particle (VLP) vaccine candidate (HIL-214) in two cohorts of children, 6-≤12 months and 1-≤4 years of age (N = 120 per cohort), in Panama and Colombia (ClinicalTrials.gov, identifier NCT02153112). On Day 1, children randomized to one of the four equal groups received intramuscular injections of four different HIL-214 formulations containing 15/15, 15/50, 50/50, or 50/150 μg of GI.1/GII.4c genotype VLPs and 0.5 mg Al(OH) 3 . On Day 29, half the children in each group received a second vaccination (N = 60), while the other half received saline placebo injections to maintain the blind. VLP-specific ELISA Pan-Ig and histo-blood group binding antigen-blocking antibodies (HBGA) were measured on Days 1, 29, 57 and 210. On Day 29, after one dose, there were large Pan-Ig and HBGA responses in both age cohorts with some indication of dose-dependence, and higher geometric mean titers (GMT) in the older children. A further increase in titers was observed 28 days after a second dose in the 6-≤12-month-old groups, but less so in the 1-≤4-year-old groups; GMTs at Day 57 were broadly similar across doses and in both age groups. GMTs of Pan-Ig and HBGA persisted above baseline up to Day 210. All formulations were well tolerated with mostly mild-to-moderate transient solicited adverse events reported by parents/guardians, and no vaccine-related serious adverse events occurred. Further development of HIL-214 is warranted to protect the most susceptible young children against norovirus.

Varicella is an acute, highly contagious disease in susceptible individuals and is preventable through vaccination. This study aimed to determine the impact of varicella vaccination on hospitalizations and complications at a pediatric reference hospital in Panama before and after the vaccine introduction. This descriptive ecological study analyzed clinical records of patients diagnosed with varicella through a retrospective and interrupted time series analysis. An autoregressive integrated moving average model was built to compare the incidence rates observed after vaccination with those expected rates derived from the model. A statistical model was fitted to the observed interrupted time series data by regression and used to predict future trends. The mean difference in varicella hospital discharges before and after the introduction of the varicella vaccine was 47%. The rate of hospitalizations for varicella decreased to 52.3%. A declining trend in varicella hospitalizations was observed from 2015 after vaccine introduction in 2014. Complications in vaccinated patients were secondary skin and soft tissue infection, possibly due to bacterial superinfection. The impact of varicella vaccination on reducing varicella hospital discharges reported at a pediatric reference hospital in Panama was confirmed.

In 2010, a 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) was introduced in the Brazilian national immunization program; the 3 + 1 dose schedule was replaced by a 2 + 1 dose schedule in 2016. This systematic review presents the latest published evidence (2015-2020) on the impact after 10-year use of PHiD-CV in Brazil from a total of 29 publications. Overall, the PHiD-CV program had a positive impact on the morbidity and mortality associated with invasive pneumococcal disease (IPD), pneumonia and acute otitis media (AOM) in children <5 years-old. A reduction in the vaccine-type invasive disease was observed in all-ages; suggesting indirect protection unvaccinated older children and adults. The occurrence of non-vaccine type disease was evidenced in some studies. Higher vaccination coverage is required at national and state level for sustained population impact. Given the change in the vaccination schedule and the dynamics of pneumococcal disease epidemiology, continuous surveillance is warranted.GSK Study identifier: HO-18-19438.

Background: Sabin strains used in oral poliovirus vaccines (OPV) can revert to virulence and, in rare instances, cause disease or generate vaccine-derived strains leading to outbreaks in areas of low immunisation coverage. A novel OPV2 (nOPV2) was designed to stabilise the viral genome against reversion and reduce recombination events that might lead to virulent strains. In this study, we evaluated the genetic and phenotypic stability of shed poliovirus following administration of one dose of monovalent OPV2 (mOPV2) or nOPV2 to infants aged 18-22 weeks., Methods: In two similarly designed clinical trials (NCT02521974 and NCT03554798) conducted in Panama, infants aged 18-22-weeks, after immunisation with three doses of bivalent OPV (types 1 and 3) and one dose of inactivated poliovirus vaccine, were administered one or two doses of mOPV2 or nOPV2. In this analysis of two clinical trials, faecally shed polioviruses following one dose of mOPV2 or nOPV2 were isolated from stools meeting predetermined criteria related to sample timing and viral presence and quantity and assessed for nucleotide polymorphisms using next-generation sequencing. A transgenic mouse neurovirulence test was adapted to assess the effect of the possible phenotypic reversion of shed mOPV2 and nOPV2 with a logistic regression model., Findings: Of the 91 eligible samples, 86 were able to be sequenced, with 72 evaluated in the transgenic mouse assay. Sabin-2 poliovirus reverts rapidly at nucleotide 481, the primary attenuation site in domain V of the 5' untranslated region of the genome. There was no evidence of neurovirulence-increasing polymorphisms in domain V of shed nOPV2. Reversion of shed Sabin-2 virus corresponded with unadjusted paralysis rates of 47·6% at the 4 log 10 50% cell culture infectious dose (CCID 50 ) and 76·7% at the 5 log 10 CCID 50 inoculum levels, with rates of 2·8% for 4 log 10 CCID 50 and 11·8% for 5 log 10 CCID 50 observed for shed nOPV2 samples. The estimated adjusted odds ratio at 4·5 log 10 of 0·007 (95% CI 0·002-0·023; p<0·0001) indicates significantly reduced odds of mouse paralysis from virus obtained from nOPV2 recipients compared with mOPV2 recipients., Interpretation: The data indicate increased genetic stability of domain V of nOPV2 relative to mOPV2, with significantly lower neurovirulence of shed nOPV2 virus compared with shed mOPV2. While this vaccine is currently being deployed under an emergency use listing, the data on the genetic stability of nOPV2 will support further regulatory and policy decision-making regarding use of nOPV2 in outbreak responses., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests We declare no competing interests. The National Institute for Biological Standards and Control, University of California, San Francisco, claim intellectual property rights associated with the nOPV2-c1. ET works for the manufacturer of nOPV2. JS and BK are employees of Viroclinics, which is paid by PATH for the conduct of next-generation sequencing and mouse neurovirulence tests. ASB was an employee of the study funder and was involved in study design and writing of the report but had no role in data collection or analysis., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Studies conducted in 1984 demonstrated the presence of Mansonella ozzardi in the Darien and Colon provinces. Since then, there have not been further reports of this parasitic infection in Panama., Methodology: We conducted a cross-sectional assessment of peripheral blood samples of individuals across Panama over a 4-year period (2013-2016) as part of malaria surveillance activities., Results: We identified microfilaria in 96 cases. Most of these cases were found in East Panama (78%) followed by the Darien region (22%). Mansonella ozzardi was the filarial parasite identified by morphological features in all cases., Conclusion: After 36 years of epidemiological silence, we identified human cases of Mansonella ozzardi infection in Panama. This is, however, the first report of this filarial parasite's presence in the Eastern region of Panama. There is a need for further surveillance efforts to elucidate the epidemiology associated with Mansonella infections in Panama., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: To meet the demand for effective and affordable inactivated polio vaccines (IPVs), a reduced dose, aluminium hydroxide (Al(OH) 3 )-adjuvanted IPV vaccine was developed (IPV-Al, Picovax®) and evaluated in clinical trials. The present trial is an extension of two previous trials (a primary and a booster trial). The aim was to evaluate the persistence of seroprotective antibodies (poliovirus type-specific antibody titre ≥ 8) in 4-year-old children who previously received IPV-Al as primary and booster vaccine doses and to determine the potential booster response and safety profile of an additional dose of IPV-Al., Methods: Children participating in the two previous trials were invited to receive one additional dose of IPV-Al at 4 years of age (2.5 years after the booster dose) and to have their blood samples collected to measure the pre- and post-vaccination antibody titres. Systemic adverse events (AEs) and local reactogenicity were recorded., Results: At study entry, the seroprotection rates were 89.2%, 100% and 91.1% against poliovirus type 1, 2 and 3, respectively. The additional vaccination with IPV-Al boosted the level of poliovirus type 1, 2 and 3 antibodies to above the seroprotection threshold for all but one subject, i.e., 99.4% for type 1 and 100% for types 2 and 3. The additional dose induced a robust booster response of a 26.3-, 13.9- and 30.9-fold increase in titre for poliovirus types 1, 2 and 3, respectively. The vaccine was well tolerated, with only mild and transient AEs reported., Conclusions: The present trial demonstrated that the primary vaccination with an aluminium-adjuvanted reduced dose IPV induced a persistent immune memory as evidenced by the robust anamnestic response when the subjects were re-exposed to the antigen 2.5 years after the last dose. Thus, the IPV-Al is an efficient and safe addition to increase the availability of inactivated polio vaccines globally. (ClinicalTrials.gov reg no. NCT04448132)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Primary intestinal immunity through viral replication of live oral vaccine is key to interrupt poliovirus transmission. We assessed viral fecal shedding from infants administered Sabin monovalent poliovirus type 2 vaccine (mOPV2) or low and high doses of 2 novel OPV2 (nOPV2) vaccine candidates., Methods: In 2 randomized clinical trials in Panama, a control mOPV2 study (October 2015 to April 2016) and nOPV2 study (September 2018 to October 2019), 18-week-old infants vaccinated with bivalent oral poliovirus vaccine/inactivated poliovirus vaccine received 1 or 2 study vaccinations 28 days apart. Stools were assessed for poliovirus RNA by polymerase chain reaction (PCR) and live virus by culture for 28 days postvaccination., Results: Shedding data were available from 621 initially reverse-transcription PCR-negative infants (91 mOPV2, 265 nOPV2-c1, 265 nOPV2-c2 recipients). Seven days after dose 1, 64.3% of mOPV2 recipients and 31.3%-48.5% of nOPV2 recipients across groups shed infectious type 2 virus. Respective rates 7 days after dose 2 decreased to 33.3% and 12.9%-22.7%, showing induction of intestinal immunity. Shedding of both nOPV2 candidates ceased at similar or faster rates than mOPV2., Conclusions: Viral shedding of either nOPV candidate was similar or decreased relative to mOPV2, and all vaccines showed indications that the vaccine virus was replicating sufficiently to induce primary intestinal mucosal immunity., Competing Interests: Potential conflicts of interest. G. A. and R. R. were full-time employees of the study sponsor; A. S. B. and J. M. were full-time employees of the Bill & Melinda Gates Foundation, which financed the study; and N. S. B. was a full-time employee of the vaccine manufacturer. All other authors report 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) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The COVID-19 vaccine candidate CVnCoV comprises sequence-optimized mRNA encoding SARS-CoV-2 S-protein encapsulated in lipid nanoparticles. In this phase 2a study, we assessed reactogenicity and immunogenicity of two or three doses in younger and older adults., Methods: Younger (18-60 years) and older (>60 years) adults were enrolled in two sites in Panama and Peru to receive either 6 or 12 µg doses of CVnCoV or licensed control vaccines 28 days apart; subsets received a 12 µg booster dose on Day 57 or Day 180. Solicited adverse events (AE) were reported for 7 days and unsolicited AEs for 4 weeks after each vaccination, and serious AEs (SAE) throughout the study. Humoral immunogenicity was measured as neutralizing and receptor binding domain (RBD) IgG antibodies and cellular immunogenicity was assessed as CD4+/CD8 + T cell responses., Results: A total of 668 participants were vaccinated (332 aged 18-60 years and 336 aged > 60 years) including 75 who received homologous booster doses. Vaccination was well tolerated with no vaccine-related SAEs. Solicited and unsolicited AEs were mainly mild to moderate and resolved spontaneously. Both age groups demonstrated robust immune responses as neutralizing antibodies or RBD-binding IgG, after two doses, with lower titers in the older age group than the younger adults. Neither group achieved levels observed in human convalescent sera (HCS), but did equal or surpass HCS levels following homologous booster doses. Following CVnCoV vaccination, robust SARS-CoV-2 S-protein-specific CD4 + T-cell responses were observed in both age groups with CD8 + T-cell responses in some individuals, consistent with observations in convalescing COVID-19 patients after natural infection., Conclusions: We confirmed that two 12 µg doses of CVnCoV had an acceptable safety profile, and induced robust immune responses. Marked humoral immune responses to homologous boosters suggest two doses had induced immune memory., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors report article publishing charges, and writing assistance were provided by CureVac AG. XS-L, CRC, RC, LE, AIG, GL-R received institutional funding for the work; GL-R received consulting fees; HJ, SDK, SL, GQ, BS and O-OW are employees of the sponsor; MG, S-KK, PM, DV, PvE-R and LO are employees of the sponsor with stock options. Other authors declare no conflicts., (© 2022 The Author(s).)

Introduction: Influenza A and B viruses constantly evolve and cause seasonal epidemics and sporadic outbreaks. Therefore, epidemiological surveillance is critical for monitoring their circulation pattern. Trivalent and quadrivalent vaccine formulations are available in Panama (until and since 2016, respectively). Herein, we analysed influenza A and B epidemiological patterns in Panama., Methods: This was a retrospective descriptive analysis of all laboratory-confirmed influenza nasopharyngeal samples recorded between 2011 and 2017 in the nationwide surveillance database of Gorgas Memorial Institute for Health Studies. The analysis involved data relative to demographic information, virus type, subtype and lineage, geographic region, treatment and outcomes. The percentage level of mismatch between circulating and vaccine-recommended B lineage was assessed for each May-October influenza season., Results: Among 1839 influenza cases, 79.6% were type A and 20.4% were type B. Most of them were observed in Panama City (54.7%) followed by the West (23.2%) and Central (16.7%) regions; across all regions, influenza A and B cases were distributed in a 4:1 ratio. Overall, approximately half were hospitalized (52.0% for type A; 45.5% for type B) and 11 (0.6%) died. Treatment, usually antimicrobial, was administered in 15.1% of cases. Children less than 2 years old were the most affected by this disease. Influenza type A circulated every year, while influenza B only circulated in 2012, 2014 and 2017. In the 2012 May-October influenza B season, the predominant lineage was B/Victoria and a switch to B/Yamagata was observed in 2014. Both lineages co-circulated in 2017, leading to a 38.9% B-lineage-level vaccine mismatch., Conclusion: Influenza A was predominant among all ages and children less than 2 years and inhabitants of Panama City reported the highest circulation rate. In 2017, co-circulation of both B lineages led to a vaccine mismatch. Continuous monitoring of seasonal influenza is critical to establish immunization recommendations., (© 2021. The Author(s).)

Background and Objectives: The burden of dengue virus (DENV), a mosquito-borne pathogen, remains difficult to assess due to misdiagnosis and underreporting. Moreover, the large proportion of asymptomatic dengue cases impairs comprehensive assessment of its epidemiology even where effective surveillance systems are in place. We conducted a prospective community-based study to assess the incidence of symptomatic dengue cases in Zapopan and neighboring municipalities in the state of Jalisco, Mexico., Methods: Healthy subjects aged 6 months to 50 years living in households located in the Zapopan and neighboring municipalities were enrolled for a 24-month follow-up study (NCT02766088). Serostatus was determined at enrolment and weekly contacts were conducted via phone calls and home visits. Participants had to report any febrile episode lasting for at least two days. Suspected dengue cases were tested by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), detection of non-structural protein 1 (NS1), anti-DENV immunoglobulin G and M (IgG and IgM) assays., Results: A total of 350 individuals from 87 households were enrolled. The overall seroprevalence of anti-DENV IgG at enrolment was 19.4% (95% confidence interval [CI] 14.5-25.6) with the highest seroprevalence rate observed in the adult group. Over the 27-month study period from July 2016 to September 2018, a total of 18 suspected dengue cases were reported. Four cases were confirmed by RT-qPCR and serotyped as DENV-1. A fifth case was confirmed by the NS1 assay. The 13 remaining suspected cases were tested negative by these assays. Based on the 5 virologically confirmed cases, symptomatic dengue incidence proportion of 1.4% (95%CI 0.5-3.8) was estimated. No severe cases or hospitalizations occurred during the study., Conclusion: Community-based active surveillance was shown as efficient to detect symptomatic dengue cases., Clinical Trial Registration: NCT02766088., Competing Interests: GlaxoSmithKline Biologicals SA (GSK) funded this study and covered all costs associated with the development and publication of this manuscript. GH, SD, MDB and AG are employees of the GSK group of companies. SD and AG hold shares in the GSK group of companies. RD was an employee of the GSK group of companies at the time of the study. GAT received payments from the GSK group of companies, as part of the multi-center study. GH, SD, MDB, AG and GAT declare no other financial and nonfinancial relationships and activities. GIN declare no financial and non-financial relationships and activities and no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials, but please note that the anonymized data is only available upon request due to privacy reasons regarding patient’s privacy and sensitive data.

In Colombia, pneumococcal conjugate vaccines (PCVs) were implemented into the infant universal mass vaccination program in a stepwise manner; PCV-7 between 2009 and 2011 in different geographic regions/cities, with nationwide introduction of a 10-valent vaccine (PHiD-CV) in 2012. We aimed to describe trends in all-cause pneumonia mortality and overall mortality, and in the incidence of all-cause pneumonia and otitis media (OM) in Colombian children <2 y (y = years) of age, before and after PCV introduction. We obtained mortality and incidence data, nationally and for five major cities (Bogota, Medellin, Barranquilla, Cali and Cartagena) from 2005-2016 and 2008-2016, respectively, comparing mortality and incidence proportions in the post-PCV introduction period with those in the pre-PCV period. Overall mean reductions in all-cause pneumonia mortality was observed in the post-PCV period nationally (48.8%; 95%CI: 45.5-51.8%) and in four cities including Bogota (77.1%; 71.1-81.8%) and Medellin (56.4%; 44.1-65.9%); no substantial reduction was observed in Cartagena. Similar findings were observed for overall mortality. Reductions in all-cause pneumonia incidence were observed in Bogota (66.0%; 65.5-66.6%), Medellin (40.6%; 39.3-41.9%) and Cartagena (15.0%; 11.2-18.6%), while incidence increased in Barranquilla (78.5%; 68.4-89.2%) and Cali (125.5%; 119.2-132.0%). All-cause OM incidence fell in Medellin and Bogota (42.1-51.1%) but increased (95.8%) in Barranquilla. In conclusion, overall reductions in disease outcomes were observed following PCV introduction in most cities and nationwide. Decreasing trends in outcomes were observed prior to PCV introduction, and limited data points and data reporting issues may have influenced our results. (ClinicalTrials.gov: NCT02567747).

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has reached 28 million cases worldwide in 1 year. The serological detection of antibodies against the virus will play a pivotal role in complementing molecular tests to improve diagnostic accuracy, contact tracing, vaccine efficacy testing, and seroprevalence surveillance. Here, we aimed first to evaluate a lateral flow assay's ability to identify specific IgM and IgG antibodies against SARS-CoV-2 and second, to report the seroprevalence estimates of these antibodies among health care workers and healthy volunteer blood donors in Panama. We recruited study participants between April 30th and July 7th, 2020. For the test validation and performance evaluation, we analyzed serum samples from participants with clinical symptoms and confirmed positive RT-PCR for SARS-CoV-2, and a set of pre-pandemic serum samples. We used two by two table analysis to determine the test positive and negative percentage agreement as well as the Kappa agreement value with a 95% confidence interval. Then, we used the lateral flow assay to determine seroprevalence among serum samples from COVID-19 patients, potentially exposed health care workers, and healthy volunteer donors. Our results show this assay reached a positive percent agreement of 97.2% (95% CI 84.2-100.0%) for detecting both IgM and IgG. The assay showed a Kappa of 0.898 (95%CI 0.811-0.985) and 0.918 (95% CI 0.839-0.997) for IgM and IgG, respectively. The evaluation of serum samples from hospitalized COVID-19 patients indicates a correlation between test sensitivity and the number of days since symptom onset; the highest positive percent agreement [87% (95% CI 67.0-96.3%)] was observed at ≥15 days post-symptom onset (PSO). We found an overall antibody seroprevalence of 11.6% (95% CI 8.5-15.8%) among both health care workers and healthy blood donors. Our findings suggest this lateral flow assay could contribute significantly to implementing seroprevalence testing in locations with active community transmission of SARS-CoV-2., Competing Interests: EO-B was employed by the GlaxoSmithKline. CL, XZ, DZ, and FF were employed by company Beijing Zhongke Jianlan Biotechnology Co., Ltd., and BW was employed by company Beijing Kewei Clinical Diagnostic Reagent Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Villarreal, Rangel, Zhang, Wong, Britton, Fernandez, Pérez, Oviedo, Restrepo, Carreirra, Sambrano, Eskildsen, De La Guardia, Flores-Cuadra, Carrera, Zaldivar, Franco, López-Vergès, Zhang, Fan, Wang, Sáez-Llorens, DeAntonio, Torres-Atencio, Blanco, Subía, Mudarra, Benzadon, Valverde, López, Hurtado, Rivas, Jurado, Carvallo, Rodriguez, Perez, Morris, Luque, Cortez, Ortega-Barria, Kosagisharaf, Lleonart, Li and Goodridge.)

Background: Hepatitis A virus (HAV) remains a global public health concern, which is potentially growing in Latin America, due to an expected shift from high to intermediate endemicity levels. The use of HAV vaccines in pediatric national immunization programs (NIPs), either as a 2-dose or a 1-dose schedule, has been explored in Latin American countries; however, evidence demonstrating long-term protection in this population is limited in the region. We evaluated long-term antibody persistence following a 1-dose partial series and the recommended 2-dose schedule used in Panama's pediatric NIP., Methods: Two independent cross-sectional serological surveys were conducted at year 8 (Y8) and Y10 following vaccination under the NIP with 1 or 2 doses of an inactivated HAV vaccine (Havrix, GSK). Seropositivity (anti-HAV antibody concentration ≥ 15 mIU/mL) rates and antibody geometric mean concentrations (GMCs) were assessed at each serosurvey. Non-inferiority of 1 dose versus 2 doses was also explored., Results: This study (NCT02712359) included 600 and 599 children at Y8 and Y10 post-vaccination, respectively. Seropositivity rates were 74.3% (95% confidence interval [CI]: 69.0; 79.2) and 97.7% (95% CI: 95.3; 99.1) at Y8 and 71.9% (95% CI: 66.4; 76.9) and 96.3% (95% CI: 93.5; 98.2) at Y10, in the 1-dose and 2-dose groups, respectively. Antibody GMCs were lower in the 1-dose versus the 2-dose group in both surveys. Non-inferiority was not demonstrated since the lower limit of the 2-sided 95% CI for the between-group difference in seropositivity rates (1-dose minus 2-dose) was < -10%., Conclusion: Anti-HAV antibody persistence was observed in lower percentages of children receiving 1 dose versus 2 doses of Havrix, at 8 and 10 years post-vaccination in Panama. Further investigations are needed to confirm antibody persistence and conclude on the protection afforded beyond 10 years in the pediatric population in Latin America., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [PJ, SaW, StW, LN, AG and CM are employee of the GSK group of companies. RDA was employee of the GSK group of companies at the time of the study. PJ, SaW, AG, hold shares or stock options in the GSK group of companies. LN reports personal fees from GSK, during the conduct of the study. StW, IA, DW, TDL, declare no competing interests.]., (Copyright © 2020 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Background: Continued emergence and spread of circulating vaccine-derived type 2 polioviruses and vaccine-associated paralytic poliomyelitis from Sabin oral poliovirus vaccines (OPVs) has stimulated development of two novel type 2 OPV candidates (OPV2-c1 and OPV2-c2) designed to have similar immunogenicity, improved genetic stability, and less potential to reacquire neurovirulence. We aimed to assess safety and immunogenicity of the two novel OPV candidates compared with a monovalent Sabin OPV in children and infants., Methods: We did two single-centre, multi-site, partly-masked, randomised trials in healthy cohorts of children (aged 1-4 years) and infants (aged 18-22 weeks) in Panama: a control phase 4 study with monovalent Sabin OPV2 before global cessation of monovalent OPV2 use, and a phase 2 study with low and high doses of two novel OPV2 candidates. All participants received one OPV2 vaccination and subsets received two doses 28 days apart. Parents reported solicited and unsolicited adverse events. Type 2 poliovirus neutralising antibodies were measured at days 0, 7, 28, and 56, and stool viral shedding was assessed up to 28 days post-vaccination. Primary objectives were to assess safety in all participants and non-inferiority of novel OPV2 day 28 seroprotection versus monovalent OPV2 in infants (non-inferiority margin 10%). These studies were registered with ClinicalTrials.gov, NCT02521974 and NCT03554798., Findings: The control study took place between Oct 23, 2015, and April 29, 2016, and the subsequent phase 2 study between Sept 19, 2018, and Sept 30, 2019. 150 children (50 in the control study and 100 of 129 assessed for eligibility in the novel OPV2 study) and 684 infants (110 of 114 assessed for eligibility in the control study and 574 of 684 assessed for eligibility in the novel OPV2 study) were enrolled and received at least one study vaccination. Vaccinations were safe and well tolerated with no causally associated serious adverse events or important medical events in any group. Solicited and unsolicited adverse events were overwhelmingly mild or moderate irrespective of vaccine or dose. Nearly all children were seroprotected at baseline, indicating high baseline immunity. In children, the seroprotection rate 28 days after one dose was 100% for monovalent OPV2 and both novel OPV2 candidates. In infants at day 28, 91 (94% [95% CI 87-98]) of 97 were seroprotected after receiving monovalent OPV2, 134 (94% [88-97]) of 143 after high-dose novel OPV2-c1, 122 (93% [87-97]) of 131 after low-dose novel OPV2-c1, 138 (95% [90-98]) of 146 after high-dose novel OPV2-c2, and 115 (91% [84-95]) of 127 after low-dose novel OPV2-c2. Non-inferiority was shown for low-dose and high-dose novel OPV2-c1 and high-dose novel OPV2-c2 despite monovalent OPV2 recipients having higher baseline immunity., Interpretation: Both novel OPV2 candidates were safe, well tolerated, and immunogenic in children and infants. Novel OPV2 could be an important addition to our resources against poliovirus given the current epidemiological situation., Funding: Fighting Infectious Diseases in Emerging Countries and Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction : Evidence on the interchangeability between the two pediatric pneumococcal conjugate vaccines (PCVs) - pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and 13-valent PCV (PCV13) - is limited but growing. We performed a systematic literature review to summarize evidence for PHiD-CV/PCV13 interchangeability regarding immunogenicity, safety, and effectiveness against pneumococcal disease. Areas covered : Seven records disclosing results from six studies on PHiD-CV/PCV13 interchangeability were identified. Four clinical trials showed that mixed schedules with a PHiD-CV-to-PCV13 switch at boosting or a PCV13-to-PHiD-CV switch during priming or at boosting were immunogenic with no apparent safety concerns. Two observational studies in the context of a programmatic PHiD-CV-to-PCV13 switch showed similarly high effectiveness against overall invasive pneumococcal disease with a mixed PHiD-CV/PCV13 schedule and a PCV13-only schedule. No effectiveness data for a PCV13-to-PHiD-CV switch and no immunogenicity/safety/effectiveness data for a PHiD-CV-to-PCV13 switch during priming were found. Expert opinion : For epidemiological or programmatic reasons, several local/national authorities have switched PCVs in their immunization programs. Consequently, children have received mixed schedules. Although herd immunity may obscure the individual effect, the limited data are reassuring. Additional evidence from these settings - especially effectiveness or impact data - may provide the necessary information for authorities to make informed decisions on interchanging PCVs.

Background: Maternal immunization with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine confers protection to young infants. We aimed to describe trends in pertussis incidence and associated mortality in children aged <12 months before and after introduction of maternal Tdap immunization in Bogotá, Colombia., Methods: Data on pertussis-related cases/deaths in infants aged <12 months were collected from SIVIGILA for the period 2005-2016, and compared incidence for the pre-vaccine introduction (2005-2012) and post-maternal Tdap vaccination (2014-2016) periods in infants aged <12 months and in three distinct age-strata; ≤6 weeks, 7-<28 weeks, and 28-52 weeks. Mortality comparisons were performed in all infants <12 months., Results: From 2005 to 2016, 2315 laboratory or clinically-confirmed pertussis cases were reported in infants <12 months of age (278 cases in young infants aged ≤6 weeks); 55 pertussis deaths were reported in children aged <12 months. No pertussis deaths were reported in the 2014-2016 period. Since maternal Tdap introduction in 2013, a consistent decline in pertussis incidence and mortality was observed. In the time-series analysis, incidence declined from 209.4/100,000 persons (2005-2012) to 49.1/100,000 persons (2014-2016) in all children <12 months; a 87.5% (95%CI: 77.2-93.2%) reduction. For these same period's incidence in young infants ≤6 weeks declined from 196.7 to 89.6/100,000 person-years (an 54.4% [95% CI: 35.4-67.9%] reduction). Greater incidence reductions were observed in older infants; 73.4% (95% CI: 68.4-77.6%) in those aged 7-<28 weeks, and 100% in those aged 28-52 weeks. A 100% reduction in Pertussis mortality in infants <12 months was observed. Since Tdap introduction, maternal vaccine coverage rose from <60% in 2013-2015 to 80% in 2016., Conclusions: Implementation of maternal immunization in Bogotá may have contributed to the reduction in pertussis incidence and mortality among infants <12 months of age (ClinicalTrials.gov: NCT02569879). An Audio Summary linked to this article that can be found on Figshare https://doi.org/10.6084/m9.figshare.12943316., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R. Devadiga, D. Caceres and P. Juliao are employees of the GSK group of companies. R. DeAntonio was an employee of the GSK group of companies at the time of this study. R. DeAntonio, D. Caceres and P. Juliao hold shares. The institution of G. Carrasquilla, A. Porras and S. Martinez (ASIESALUD) received financial support from the GSK group of companies for the conduct of this study. This work was supported by GSK Biologicals SA., which was involved in study design, data collection, analysis and interpretation, as well as decision to publish., (Copyright © 2020 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Background: An unmet clinical need remains for an effective tetravalent dengue vaccine suitable for all age groups, regardless of serostatus. We assessed the immunogenicity and safety of three different dose schedules of a tetravalent dengue vaccine (TAK-003) over a 48-month period in children living in dengue-endemic countries., Methods: We did a large, phase 2, double-blind, placebo-controlled trial at three sites in the Dominican Republic, Panama, and the Philippines. Healthy participants aged 2-17 years were randomly assigned 1:2:5:1 using an interactive web response system with stratification by age to receive either a two-dose primary series (days 1 and 91), one primary dose (day 1), one primary dose plus booster (days 1 and 365), or placebo. Participants and relevant study personnel were masked to the random assignment until completion of the study at month 48. To maintain masking, TAK-003 recipients were administered placebo doses when appropriate. The primary objective was assessment of neutralising geometric mean titres for each serotype to month 48 assessed in the per-protocol immunogenicity subset. Secondary safety endpoints included proportions of participants with serious adverse events and symptomatic virologically confirmed dengue. This study is registered with ClinicalTrials.gov, NCT02302066., Findings: Between Dec 5, 2014, and Feb 13, 2015, 1800 children were randomly assigned to the following groups: two-dose primary series (n=201), one primary dose (n=398), one primary dose plus 1-year booster (n=1002), and placebo (n=199). Of them, 1479 (82%) participants completed the 48-month study. Immunogenicity endpoints were assessed in 562 participants enrolled in the immunogenicity subset, of whom 509 were included in the per-protocol subset. At month 48, antibody titres remained elevated in all TAK-003 groups compared with placebo, irrespective of baseline serostatus. At month 48, geometric mean titres were 378 (95% CI 226-632) in two-dose, 421 (285-622) in one-dose, 719 (538-960) in one-dose plus 1-year booster, and 100 (50-201) in placebo recipients against DENV 1; 1052 (732-1511), 1319 (970-1794), 1200 (927-1553), and 208 (99-437) against DENV 2; 183 (113-298), 201 (135-298), 288 (211-392), and 71 (37-139) against DENV 3; and 152 (97-239), 164 (114-236), 219 (165-290), and 46 (26-82) against DENV 4; and tetravalent seropositivity rate was 89% (79-96), 86% (80-92), 97% (93-99), and 60% (47-72), respectively. Virologically confirmed dengue was recorded in 37 (2%) TAK-003 and 13 (7%) placebo participants, with a relative risk of 0·35 (0·19-0·65). No vaccine-related serious adverse events or severe dengue virus disease were reported., Interpretation: TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. No important safety risks were identified. We observed a long-term reduction in risk of symptomatic dengue virus disease in vaccinees. Results from this study provide a long-term safety database and support assessment of the vaccine in the ongoing phase 3 efficacy study., Funding: Takeda Vaccines., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Cost-effectiveness analysis (CEA) is the economic analysis method most commonly applied today in the context of replacing one treatment with a new one in a developed healthcare system to improve efficiency. CEA is often requested by local healthcare decision-makers to grant reimbursement. New preventative interventions, such as new vaccines, may however have much wider benefits inside and outside healthcare, when compared with treatment. These additional benefits include externalities on indirect clinical impact, reallocation of specific healthcare resources, improved quality of care, better productivity, better disease control, better fiscal revenues, and others. But these effects are sometimes difficult to integrate into a meaningful CEA result. They may appear as specific benefits for specific stakeholders, other than the stakeholders in healthcare. Objective: Based on a historical view about the application of economic assessments for vaccines our objective has been to make the inventory of who was/is interested in knowing the economic value of vaccines, in what those different stakeholders are likely to see the benefit from their perspective and how  were/are we able to measure those benefits and to report them well. Results: The historical view disclosed a limited interest in the economic assessment of vaccines at start, more than 50 years ago, that was comparable to the assessment of looking for more efficiency in new industries through optimization exercises. Today, we are exposed to a very rich panoply of different stakeholders (n= 16). They have their specific interest in many different facets of the vaccine benefit of which some are well known in the conventional economic analysis (n=9), but most outcomes are hidden and not enough evaluated and reported (n=26). Meanwhile we discovered that many different methods of evaluation have been explored to facilitate the measurement and reporting of the benefits (n=18). Conclusion: Our recommendation for future economic evaluations of new vaccines is therefore to find the right combination among the three entities of stakeholder type selection, outcome measure of interest for each stakeholder, and the right method to apply. We present at the end examples that illustrate how successful this approach can be., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Current vaccination coverage rates in Latin America and the Caribbean (LAC) are lower than the region-wide rates set by the Pan American Health Organization. To improve vaccination uptake, it is crucial to identify barriers to vaccination. We conducted a systematic literature review to identify the key barriers to vaccination in the LAC region, and to classify and quantify factors affecting vaccination coverage using the barrier categories outlined by the Strategic Advisory Group of Experts (SAGE) working group. We mapped knowledge gaps in the understanding of region-specific and population-specific vaccine hesitancy. Nine databases (Medline via PubMed, Web of Science, LILACS, MedCarib, SciELO, Scopus, PATH, SAGE Online and Google Scholar) were searched for articles published in English, Spanish and Portuguese up to 15 July 2017. A total of 6867 articles were identified of which 75 were included in the review. Majority of the articles were quantitative in nature and nearly half from Brazil. Many other countries in LAC have limited published evidence on barriers to vaccination. The most commonly investigated target population was parents (of children <8 years of age [yoa] and adolescents 9-10 yoa) but there was a balance in the number of publications that reported on influenza, childhood and human papillomavirus vaccination. There was limited direct evidence which reported insights on the new generation of childhood vaccines (pneumococcal or meningococcal vaccines) or studies targeting adolescents and pregnant women. Among the SAGE barrier categories, 'individual/group influences' were the most frequently reported barrier category (68%) followed by 'contextual influences' (47%). Adverse socioeconomic factors, a low level of education, lack of awareness of diseases and their vaccines, religious and cultural beliefs are commonly cited as obstacles to vaccination acceptance. Additional evidence is needed to fully understand the barriers to vaccination for different target populations, countries in the region and specific vaccine types., (Copyright © 2019 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Objective: To identify the main risk factors associated with neonatal candidemia., Patients and Method: A retrospective paired case-control study was conducted from January 2014 to December 2016. The cases were patients with isolation in blood culture and/or cerebrospinal fluid of Candi da spp. after their first 48 hours in the hospital and the controls cases were neonates chosen from the statistical census of neonatology paired according to their admission date (30-day range), birth weight, gestational age, and discharge condition (alive or deceased). For each case, we select two controls. The risk factors evaluated were intrahospital stay over seven days, use of broad-spectrum antibiotics, mechanical ventilation, parenteral nutrition longer than five days, invasive procedures such as central venous access and abdominal and thoracic surgeries, necrotizing enterocolitis and growth of bacterial microorganisms in blood culture before candidemia., Results: During the study period, 141 patients developed candidemia. 49% of the cases corresponded to Candida parapsilosis with the highest associated lethality rate. The multivariate analysis identified as risk factors hospital stay longer than seven days (OR = 17.0, 95% CI = 2.36-122.4), use of umbilical lines (OR = 9.04, 95% CI = 1.55-52.5), abdominal and/or thoracic surgery (OR = 12.4, 95% CI = 1.76-87.3), and treatment with Meropenem (OR = 4.62, 95% CI = 1.34-15.9)., Conclusion: Prolonged intrahospital stay longer than seven days and thoracic and/or abdominal surgery were the most significant risk factors in this study for the development of neonatal candidemia.

Background: National pediatric vaccination programs have been introduced in Latin America (LatAm) to reduce the burden of diseases due to pathogens such as rotavirus, Haemophilus influenzae type b (Hib) and pneumococcus. Vaccination health benefits may extend to unvaccinated populations by reducing pathogen transmission. Understanding herd effect is important for implementation and assessment of vaccination programs. The objective was to conduct a systematic review of published epidemiological evidence of herd effect with Hib, rotavirus and pneumococcal conjugate vaccines (PCV) in LatAm., Methods: Searches were conducted in PubMed, Virtual Health Library (VHL), SciELO and SCOPUS databases, for studies reporting data on herd effect from Hib, rotavirus and PCV vaccination in LatAm, without age restriction. Searches were limited to articles published in English, Spanish or Portuguese (1990-2016). After screening and full-text review, articles meeting the selection criteria were included to be critically appraised following criteria for observational and interventional studies. The presence of a herd effect was defined as a significant decrease in incidence of disease, hospitalization, or mortality., Results: 3,465 unique articles were identified, and 23 were included (Hib vaccine n = 5, PCV n = 8, rotavirus vaccine n = 10). Most studies included children and/or adolescents (age range varied between studies). Studies in adults, including older adults (aged > 65 years), were limited. Few studies reported statistically significant reductions in disease incidence in age groups not targeted for vaccination. Hib-confirmed meningitis hospitalization decreased in children but herd effect could not be quantified. Some evidence of herd effect was identified for PCV and rotavirus vaccine in unvaccinated children. Evidence for herd effects due to PCV in adults was limited., Conclusion: After introduction of Hib, PCV and rotavirus vaccination in LatAm, reductions in morbidity/mortality have been reported in children not targeted for vaccination. However, due to methodological limitations (e.g. short post-vaccination periods and age range studied), there is currently insufficient evidence to quantify the herd effect in adult populations. More research and higher quality surveillance is needed to characterize herd effect of these vaccines in LatAm.

Worldwide, rotavirus infection has been a leading cause of severe diarrhea morbidity and mortality. Two rotavirus vaccines have been used in the National Immunization Program (NIP) in Mexico; two-dose Rotarix from 2006 to 2011 and three-dose RotaTeq since 2011. This study assessed coverage (receiving at least one dose or full dose series) in eligible infants, compliance (% completing dose series and % completing series on schedule) in eligible infants vaccinated with Rotarix (2010) versus RotaTeq (2012), using Mexican Social Security Institute data nationwide and by regions. In 2010, 80.7% received at least one dose of Rotarix , 75.6% received both doses and 57.0% received both doses on schedule. In 2012, 85.7% received at least one dose of RotaTeq , 61.0% received all three doses and 43.2% received all three doses on schedule. More eligible infants received all doses with Rotarix versus RotaTeq (p < 0.001). Among infants vaccinated with Rotarix versus RotaTeq , 93.7% versus 71.1% completed full series (p < 0.001), and 75.5% versus 70.9% completed full series on schedule (p = 0.105), respectively. The full series coverage and compliance decreased in all regions with RotaTeq compared with Rotarix . In conclusion, rotavirus vaccination has successfully reduced morbidity and mortality in children under 5 years in Mexico. This study found significant differences in full series coverage and compliance among infants and a higher proportion of completed scheduled at an earlier age in Mexico when comparing a two-dose vaccine in 2010 with a three-dose vaccine in 2012. Such differences might need to be taken into consideration to maximize NIP benefits, including early protection of the rotavirus vaccination program.

Objectives: To estimate hepatitis B virus (HBV) seroprevalence from natural infection or vaccination in 10-25-year-olds in Mexico, using the 2012 National Health and Nutrition Survey (ENSANUT)., Methods: Randomly selected serum samples (1,581) from adolescents and young adults, representative of 38,924,584 Mexicans, were analyzed to detect hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc). Weighted HBV seroprevalence in the Mexican population and association with sociodemographic variables were calculated., Results: Overall weighted seroprevalence from natural infection (positive for anti-HBs and anti-HBc) was 0.23% (95% confidence interval [95% CI] 0.10-0.52). No HBsAg was detected, indicating no acute or chronic infection. Vaccine-derived immunity (positive ≥ 10.0 mIU/ml for anti-HBs and negative to anti-HBc) was 44.7% (95% CI: 40.2-49.4) overall; lower in persons aged 20-25 years (40.83%) than in persons aged 10-19 years (47.7%). Among the population analyzed, 54.2% (95% CI: 49.6-58.8) were seronegative to HBV (negative for all three markers) and no sociodemographic risk factors were identified., Conclusions: HBV seroprevalence from natural infection was low. Vaccination-induced immunity was higher among Mexican adolescents than young adults, possibly due to vaccination policies since 1999.

To describe hepatitis A virus (HAV) seroprevalence and associated factors in adolescents (10-19 years) and young adults (20-25 years) in different Mexican regions, using 2012 National Health and Nutrition Survey data. A random selection of 1581 serum samples was analyzed. Weighted HAV seroprevalence with 95% confidence intervals (95%CI) and its association with sociodemographic factors were estimated. Mean weighted HAV seroprevalence was 69.3% (95%CI: 64.8-73.4) overall, with 58.8% (95%CI: 53.4-64.1) in adolescents and 83.0% (95%CI: 75.3-88.7) in young adults. By age of 10, 46.7% (95%CI: 33.9-60.0) were seropositive and by age of 15, 52.8% (95%CI: 36.5-68.5), corresponding to intermediate endemicity nationally. Factors associated with HAV seropositivity (adjusted odds ratio, aOR) included: lower socioeconomic status (SES) (aOR = 4.09 for low and aOR = 2.31 for medium versus high SES), older age (aOR = 0.29 for adolescents versus young adults), living in the South (aOR = 2.12 versus Central Mexico) or in rural areas (aOR = 2.25 versus urban areas). Regional differences and increased seroprevalence of HAV in marginalized populations present an important public health issue, as a relatively large proportion of young adults are susceptible to infection. The burden of symptomatic disease must be addressed further to support specific programs of continued sanitation and education improvement, and the possibility of vaccination in more susceptible regions., (Copyright © 2018 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Background: This systematic review aims to describe the prevalence, trends, and antibiotic resistance of Streptococcus pneumoniae serotype 19A (Spn19A) that causes invasive and non-invasive diseases in children <5 years in Latin-American and Caribbean countries., Methods: We searched for published (between January 2010 and February 2016) observational and clinical studies within the region including effectiveness and impact on Spn19A after pneumococcal conjugate vaccine (PCV) introduction. We calculated prevalence estimates by country and standardized the frequency of isolates to conduct an interrupted time series analysis for selected countries and to assess the potential changes in disease trends, overall and for Spn19A., Results: We identified and reviewed full-text of 89 publications and included 59 in the analysis. Data from the laboratory surveillance network, SIREVA, were included in 43 (74%) of the invasive pneumococcal disease reports. There are differences in the sensitivity, representativeness, and heterogeneity of laboratory surveillance. There has been and overall reduction in the trend and number of invasive S. pneumoniae isolates in children <5 years after PCVs introduction. To date, the prevalence of Spn19A has increased, however, there has been no observed change in the trend., Conclusions: This updated systematic review provides evidence of a reduction in the total number of invasive pneumococcal disease isolates after the introduction of PCVs in the region but cannot yet conclude a change in the trend of Spn19A disease., (Copyright © 2018. Published by Elsevier Ltd.)

Colombia introduced mass pneumococcal conjugate vaccination at the end of 2011. Using 2005-2015 surveillance data, we conducted a retrospective interrupted time-series analysis. A significant trend towards reduced monthly was observed in the post-vaccination period (2012-2015) compared with the expected rate, reaching in 2015 a reduction of 90.5% of pneumococcal meningitis. This trend was not observed for control diseases.

Varicella-zoster virus causes varicella (chicken-pox), mainly in young children. Most cases are mild but serious complications can occur, resulting in significant morbidity and mortality. The objective of this study was to estimate the cost burden of varicella hospitalizations in two pediatric reference hospitals in Mexico. This retrospective observational study collected data on patients aged <18 years admitted to two third-level referral hospitals in Mexico. Cases were identified from hospital records using International Classification of Diseases Ninth Revision (ICD-9) codes 052 Chickenpox, or Tenth Revision (ICD-10) codes B01 Varicella (chickenpox). Data on demographic and clinical characteristics and resource use were collected from hospital records. Costs for hospital stay and interventions were obtained from the Mexican Institute for Social Security for 2015 and updated to 2017 costs. A total of 172 hospitalized varicella clinically-confirmed cases and 121 varicella- contacts (with epidemiological linkage to a clinically-confirmed case) were included. Thirty eight of the 172 cases (22.0%) experienced complications. There were no deaths. The median duration of hospitalization was 12 days for cases and 23 days for contacts. The median hospitalization cost was MXN 82,572 (USD 4,434) per case, and MXN 89,453 (USD 4,804) per contact. Although considered a mild disease, varicella was associated with a substantial cost burden in two Mexican third-level referral hospitals.