Confronting the challenge: a regional perspective by the Latin American pediatric infectious diseases society (SLIPE) expert group on respiratory syncytial virus-tackling the burden of disease and implementing preventive solutions.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in children around the world. The post-pandemic era has resulted in a notable increase in reported cases of RSV infections, co-circulation of other respiratory viruses, shifts in epidemiology, altered respiratory season timing, and increased healthcare demand. Low- and middle-income countries are responsible for the highest burden of RSV disease, contributing significantly to health expenses during respiratory seasons and RSV-associated mortality in children. Until recently, supportive measures were the only intervention to treat or prevent RSV-infection, since preventive strategies like palivizumab are limited for high-risk populations. Advances in new available strategies, such as long-acting monoclonal antibodies during the neonatal period and vaccination of pregnant women, are now a reality. As the Regional Expert Group of the Latin American Pediatric Infectious Diseases Society (SLIPE), we sought to evaluate the burden of RSV infection in Latin America and the Caribbean (LAC) region, analyze current strategies to prevent RSV infection in children, and provide recommendations for implementing new strategies for preventing RSV infection in children in LAC region.

Norovirus in children under 2 years of age: an epidemiological study in Panama during the COVID-19 pandemic.

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.

Are the first 1,000 days of life a neglected vital period to prevent the impact on maternal and infant morbimortality of infectious diseases in Latin America? Proceedings of a workshop of experts from the Latin American Pediatric Infectious Diseases Society, SLIPE.

While the first 1,000 days of life are a critical period in child's development, limited information on the main determinants affecting this period in the Latin America and the Caribbean (LAC) region is available. Therefore, the Latin American Pediatric Infectious Diseases Society (SLIPE) held an ad hoc workshop in May 2022 with an expert panel designed to analyze the main factors impacting the development of childhood in the region during this period and the main causes of maternal infant morbimortality. The aim was to identify priorities, generate recommendations, and advise practical actions to improve this situation. Considerations were made about the challenges involved in bridging the gap that separates the region from more developed countries regarding an optimal early childhood and maternal care. Extensive discussion was conducted to reach consensus recommendations on general strategies intended to reduce maternal and infant mortality associated with infections and immune-preventable diseases during the first 1,000 days of life in LAC.

Immunogenicity and tolerability of a bivalent virus-like particle norovirus vaccine candidate in children from 6 months up to 4 years of age: A phase 2 randomized, double-blind trial.

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.

Corrigendum to "Safety and immunogenicity of mRNA-LNP COVID-19 vaccine CVnCoV in Latin American adults: A phase 2 randomized study" [Vaccine: X 11 (2022) 100189].

[This corrects the article DOI: 10.1016/j.jvacx.2022.100189.].

Genetic and phenotypic stability of poliovirus shed from infants who received novel type 2 or Sabin type 2 oral poliovirus vaccines in Panama: an analysis of two clinical trials.

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 log10 50% cell culture infectious dose (CCID50) and 76·7% at the 5 log10 CCID50 inoculum levels, with rates of 2·8% for 4 log10 CCID50 and 11·8% for 5 log10 CCID50 observed for shed nOPV2 samples. The estimated adjusted odds ratio at 4·5 log10 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.

Persistence of protective anti-poliovirus antibody levels in 4-year-old children previously primed with Picovax®, a trivalent, aluminium-adjuvanted reduced dose inactivated polio vaccine.

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).

Safety and immunogenicity of mRNA-LNP COVID-19 vaccine CVnCoV in Latin American adults: A phase 2 randomized study.

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.

Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003).

BACKGROUND: Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data. METHODS: Healthy 4-16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction. RESULTS: Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6-66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8-88.4) against hospitalized VCD. Efficacy was 54.3% (41.9-64.1) against VCD and 77.1% (58.6-87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9-70.1) against VCD and 86.0% (78.4-91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5-54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6-83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified. CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination.

BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. METHODS: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. RESULTS: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. CONCLUSIONS: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries.

Performance of a Point of Care Test for Detecting IgM and IgG Antibodies Against SARS-CoV-2 and Seroprevalence in Blood Donors and Health Care Workers in Panama.

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.

Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in children and infants: two clinical trials.

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.

Safety and immunogenicity of inactivated poliovirus vaccine schedules for the post-eradication era: a randomised open-label, multicentre, phase 3, non-inferiority trial.

BACKGROUND: Following the global eradication of wild poliovirus, countries using live attenuated oral poliovirus vaccines will transition to exclusive use of inactivated poliovirus vaccine (IPV) or fractional doses of IPV (f-IPV; a f-IPV dose is one-fifth of a normal IPV dose), but IPV supply and cost constraints will necessitate dose-sparing strategies. We compared immunisation schedules of f-IPV and IPV to inform the choice of optimal post-eradication schedule. METHODS: This randomised open-label, multicentre, phase 3, non-inferiority trial was done at two centres in Panama and one in the Dominican Republic. Eligible participants were healthy 6-week-old infants with no signs of febrile illness or known allergy to vaccine components. Infants were randomly assigned (1:1:1:1, 1:1:1:2, 2:1:1:1), using computer-generated blocks of four or five until the groups were full, to one of four groups and received: two doses of intradermal f-IPV (administered at 14 and 36 weeks; two f-IPV group); or three doses of intradermal f-IPV (administered at 10, 14, and 36 weeks; three f-IPV group); or two doses of intramuscular IPV (administered at 14 and 36 weeks; two IPV group); or three doses of intramuscular IPV (administered at 10, 14, and 36 weeks; three IPV group). The primary outcome was seroconversion rates based on neutralising antibodies for poliovirus type 1 and type 2 at baseline and at 40 weeks (4 weeks after the second or third vaccinations) in the per-protocol population to allow non-inferiority and eventually superiority comparisons between vaccines and regimens. Three co-primary outcomes concerning poliovirus types 1 and 2 were to determine if seroconversion rates at 40 weeks of age after a two-dose regimen (administered at weeks 14 and 36) of intradermally administered f-IPV were non-inferior to a corresponding two-dose regimen of intramuscular IPV; if seroconversion rates at 40 weeks of age after a two-dose IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose IPV regimen (weeks 10, 14, and 36); and if seroconversion rates after a two-dose f-IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose f-IPV regimen (weeks 10, 14, and 36). The non-inferiority boundary was set at -10% for the lower bound of the two-sided 95% CI for the seroconversion rate difference.. Safety was assessed as serious adverse events and important medical events. This study is registered on ClinicalTrials.gov, NCT03239496. FINDINGS: From Oct 23, 2017, to Nov 13, 2018, we enrolled 773 infants (372 [48%] girls) in Panama and the Dominican Republic (two f-IPV group n=217, three f-IPV group n=178, two IPV group n=178, and three IPV group n=200). 686 infants received all scheduled vaccine doses and were included in the per-protocol analysis. We observed non-inferiority for poliovirus type 1 seroconversion rate at 40 weeks for the two f-IPV dose schedule (95·9% [95% CI 92·0-98·2]) versus the two IPV dose schedule (98·7% [95·4-99·8]), and for the three f-IPV dose schedule (98·8% [95·6-99·8]) versus the three IPV dose schedule (100% [97·9-100]). Similarly, poliovirus type 2 seroconversion rate at 40 weeks for the two f-IPV dose schedule (97·9% [94·8-99·4]) versus the two IPV dose schedule (99·4% [96·4-100]), and for the three f-IPV dose schedule (100% [97·7-100]) versus the three IPV dose schedule (100% [97·9-100]) were non-inferior. Seroconversion rate for the two f-IPV regimen was statistically superior 4 weeks after the last vaccine dose in the 14 and 36 week schedule (95·9% [92·0-98·2]) compared with the 10 and 14 week schedule (83·2% [76·5-88·6]; p=0·0062) for poliovirus type 1. Statistical superiority of the 14 and 36 week schedule was also found for poliovirus type 2 (14 and 36 week schedule 97·9% [94·8-99·4] vs 10 and 14 week schedule 83·9% [77·2-89·2]; p=0·0062), and poliovirus type 3 (14 and 36 week schedule 84·5% [78·7-89·3] vs 10 and 14 week schedule 73·3% [65·8-79·9]; p=0·0062). For IPV, a two dose regimen administered at 14 and 36 weeks (99·4% [96·4-100]) was superior a 10 and 14 week schedule (88·9% [83·4-93·1]; p<0·0001) for poliovirus type 2, but not for type 1 (14 and 36 week schedule 98·7% [95·4-99·8] vs 10 and 14 week schedule 95·6% [91·4-98·1]), or type 3 (14 and 36 week schedule 97·4% [93·5-99·3] vs 10 and 14 week schedule 93·9% [89·3-96·9]). There were no related serious adverse events or important medical events reported in any group showing safety was unaffected by administration route or schedule. INTERPRETATION: Our observations suggest that adequate immunity against poliovirus type 1 and type 2 is provided by two doses of either IPV or f-IPV at 14 and 36 weeks of age, and broad immunity is provided with three doses of f-IPV, enabling substantial savings in cost and supply. These novel clinical data will inform global polio immunisation policy for the post-eradication era. FUNDING: Bill & Melinda Gates Foundation.

Médicos en Pandemia / Physicians in pandemic

La vocación hipocrática es una actitud de vida dedicada a la atención altruista de los demás, presente en los médicos antes de iniciar la carrera, pero profundizada a lo largo de la actividad profesional, haciéndose más relevante en circunstancias riesgosas como la que vivimos actualmente.

The Hippocratic vocation is an attitude of life dedicated to the altruistic care of others, present in doctors before starting the career, but deepened throughout the professional activity, becoming more relevant in risky circumstances such as the one we live today.

Immunogenicity and safety of an adjuvanted inactivated polio vaccine, IPV-Al, following vaccination in children at 2, 4, 6 and at 15-18 months.

BACKGROUND: Availability of affordable inactivated polio vaccines (IPV) is of major importance to meet the increasing global supply needs. The results presented here demonstrate non-inferiority of a reduced-dose, aluminium hydroxide-adjuvanted IPV (IPV-Al) to standard IPV. METHODS: A phase 3, observer-blinded, randomised, clinical trial was conducted in Panama in infants who received either IPV-Al (n = 400) or standard IPV (n = 400) at age 2, 4 and 6 months. In the booster trial, subjects received a single dose of IPV-Al at age 15-18 months. The primary endpoint was type-specific seroconversion, defined as an antibody titre ≥4-fold higher than the estimated maternal antibody titre and a titre ≥8, one month after the primary vaccination series. In the booster trial, the primary endpoint was the type-specific booster effects (geometric mean titre (GMT) post-booster (Day 28)/GMT pre-booster (Day 0). RESULTS: Seroconversion rates following primary vaccination with IPV-Al vs IPV were: 96.1% vs 100% (type 1); 100% vs 100% (type 2); and 99.2% vs 100% (type 3) respectively. IPV-Al was non-inferior to IPV, as the lower 95% confidence limits of the treatment differences were above the pre-defined -10%-point limit: 3.94% (-6.51; -2.01) for type 1; 0.0% (-1.30; -1.37) for type 2; -0.85 (-2.46; 0.40) for type 3. The booster effects for the group primed with IPV-Al versus the group primed with IPV were 25.3 vs 9.2 (type 1), 19.1 vs 6.5 (type 2) and 50.4 vs 12.5 (type 3). IPV-Al had a comparable safety profile to that of IPV. CONCLUSIONS: Non-inferiority of IPV-Al to standard IPV with respect to seroconversion after vaccination at 2, 4 and 6 months was confirmed for all three poliovirus serotypes. A robust booster response was demonstrated following vaccination with IPV-Al, regardless of the primary vaccine received. Both vaccines were well tolerated. ClinicalTrials.gov identifiers: NCT03025750 and NCT03671616. FUNDING: Bill & Melinda Gates Foundation.

Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years. METHODS: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo. INTERPRETATION: TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance. FUNDING: Takeda Vaccines.

Safety and immunogenicity of a tetravalent dengue vaccine in children aged 2-17 years: a randomised, placebo-controlled, phase 2 trial.

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.

[Risk factors and lethality associated with neonatal candidemia in a neonatal unit]. / Factores de riesgo y letalidad asociados a candidemia neonatal en una unidad de neonatología.

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.

Factores de riesgo y letalidad asociados a candidemia neonatal en una unidad de neonatología / Risk factors and lethality associated with neonatal candidemia in a neonatal unit

OBJETIVO: Determinar los principales factores de riesgo asociados a candidemia en neonatos. PACIENTES Y MÉTODO: Se realizó un estudio de casos y controles retrospectivo pareado, desde enero de 2014 a diciembre de 2016. Los casos fueron pacientes con aislamiento en hemocultivo y/o líquido cefalorraquídeo de Candida spp. luego de sus primeras 48 horas intrahospitalarias y los controles fueron neonatos escogidos del censo estadístico de la sala de neonatología pareados según su fecha de admisión a sala (rango de 30 días), peso al nacer, edad gestacional y condición de egreso (vivo o fallecido). Por cada caso seleccionamos dos controles. Los factores de riesgo evaluados fueron la estancia intrahospitalaria mayor a 7 días, el uso de antibióticos de amplio espectro, ventilación mecánica, nutrición parenteral mayor a 5 días, procedimientos invasivos como colocación de accesos venosos centrales y cirugías abdominales y torácicas, enterocolitis necrosante y crecimiento de microorganismo bacteriano en hemocultivo previo a la candidemia. RESULTADOS: Durante el período de estudio hubo aislamiento de Candida spp. en 141 neonatos. Se encontró que el 49% fue de Candida parapsilosis con la mayor letalidad asociada. En el análisis multivariado se identificaron como factores de riesgo la estancia intrahospitalaria mayor a 7 días (OR = 17,0, 95% IC = 2,36-122,4), uso de líneas umbilicales (OR = 9,04, 95% IC = 1,55-52,5), exposición a cirugía (OR = 12,4, 95% IC = 1,76-87,3) y el uso de meropenem (OR = 4,62, 95% IC = 1,34-15,9). CONCLUSIÓN: La estancia intrahospitalaria prolongada mayor a 7 días y la exposición a cirugía fueron los factores de riesgo más importantes en este estudio para el desarrollo de candidemia neonatal.

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 Candida 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.