Streptococcus pneumoniae serotype 19A in hospitalized children with invasive pneumococcal disease after the introduction of conjugated vaccines in Lima, Peru.

BACKGROUND: The Pneumococcal conjugate vaccine (PCV) has decreased cases of invasive pneumococcal disease (IPD) worldwide. However, the impact of PCVs introduction may be affected by the serotype distribution in a specific context. METHODS: Cross-sectional multicenter passive surveillance study of IPD cases in pediatric patients hospitalized in Lima, Peru between 2016 and 2019 (after PCV13 introduction) to determine the serotype distribution and antimicrobial resistance of Streptococcus pneumoniae. Serotyping was performed by a sequential multiplex PCR and confirmed by whole genome sequencing. RESULTS: Eighty-five S. pneumoniae isolates were recovered (4.07/100,000 among children <60 months of age). Serotype 19A was the most common (49.4%). Children infected with serotype 19A in comparison with children infected with other serotypes were younger, had a lower rate of meningitis and higher rates of pneumonia, complicated pneumonia and antimicrobial resistance; 28.6% of patients with serotype 19A have received at least one dose of PCV13 vs. 62.8% of patients with other serotypes. Using MIC-breakpoints, 81.2% (56/69) of non-meningitis strains and 31.2% (5/16) of meningitis strains were susceptible to penicillin; 18.8% (3/16) of meningitis strains had intermediate resistance to ceftriaxone. Resistance to azithromycin was 78.8% (67/85). Serotype 19A frequency increased over time in the same study population, from 4.2% (4/96) in 2006-2008, to 8.6% (5/58) in 2009-2011, to 49.4% (42/85) in the current study (2016-2019) (p < 0.001). CONCLUSIONS: After PCV13 introduction in Peru, serotype 19A remains the most prevalent; however, the vaccination coverage is still not optimal. Therefore, additonal surveillance studies are needed to determine the remaining IPD burden.

Oral lactoferrin administration does not impact the diversity or composition of the infant gut microbiota in a Peruvian cohort.

IMPORTANCE: Previous studies have suggested that oral lactoferrin enhances diversity in the gut microbiota in infants while inhibiting the growth of opportunistic pathogens. However, the effect of lactoferrin on infant gut microbiota over time has yet to be thoroughly studied. Our study suggests that lactoferrin oral treatment in infants aged 12-18 months does not affect gut microbiome diversity and composition over time. To our knowledge, this is the first study to report the effect of lactoferrin on infant gut microbiome composition over time and helps elucidate its impact on infant health and its therapeutic potential.

Cryptosporidium infection and associated risk factors among children from rural areas in Peru: a nested case-control study.

This study aimed to detect the frequency of Cryptosporidium infection and associated risk factors among children from rural areas in Peru. A case-control study was conducted, nested in a cohort in two rural communities that included children between 6 and 13 months who were followed for 6 months. Cases were children whose fecal samples tested positive for Cryptosporidium infection using an immunochromatography test. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to analyze risk factors associated with Cryptosporidium infection. Among 72 children, 13 (18%) were cases. Cryptosporidium infection was associated with below secondary education of the mother (OR 7.62, 95% CI 1.50-36.72) and with having more siblings living at home (OR 1.71, 95% CI 1.04-2.82). An important frequency of Cryptosporidium infection among children from rural areas in Peru was reported, more research is needed to understand its true burden and risk factors among children in Peru.

Pneumococcal serotypes and antibiotic resistance in healthy carriage children after introduction of PCV13 in Lima, Peru.

OBJECTIVE: To determinate the frequency of Streptococcus pneumoniae nasopharyngeal carriers, serotypes and antimicrobial resistance in healthy children in Lima, Peru, post-PCV13 introduction and to compare the results with a similar study conducted between 2006 and 2008 before PCV7 introduction (pre-PCV7). METHODS: A cross-sectional multicenter study was conducted between January 2018 and August 2019 in 1000 healthy children under two years of age. We use standard microbiological methods to determinate S. pneumoniae from nasopharyngeal swab, Kirby Bauer and minimum inhibitory concentration methods to determinate antimicrobial susceptibility and whole genomic sequencing to determinate pneumococcal serotypes. RESULTS: The pneumococcal carriage rate was 20.8 % vs. 31.1 % in pre-PCV7 (p < 0.001). The most frequent serotypes were 15C, 19A and 6C (12.4 %, 10.9 % and 10.9 % respectively). The carriage of PCV13 serotypes after PCV13 introduction decreased from 59.1 % (before PCV7 introduction) to 18.7 % (p < 0.001). Penicillin resistance was 75.5 %, TMP/SMX 75.5 % and azithromycin 50.0 %, using disk diffusion. Penicillin resistance rates using MIC breakpoint for meningitis (MIC ≥ 0.12) increased from 60.4 % to 74.5 % (p = 0.001). CONCLUSION: The introduction of PCV13 in the immunization program in Peru has decreased the pneumococcal nasopharyngeal carriage and the frequency of PCV13 serotypes; however, there has been an increase in non-PCV13 serotypes and antimicrobial resistance.

Knowledge, Attitudes, and Practices Concerning Maternal Immunization Among Pregnant/Postpartum Women and Health Care Professionals in Peru.

INTRODUCTION: For pregnant women, vaccination with inactivated influenza vaccine (IIV) and tetanus, diphtheria, acellular pertussis vaccine (Tdap) is recommended. In Peru, uptake is nonetheless low. A study was conducted to identify factors affecting maternal vaccination coverage. The study's primary objectives were to describe the knowledge, attitudes, and practices regarding maternal immunization among pregnant/postpartum women and health care professionals (HCPs). The secondary objective was to determine the vaccination coverage and the impact of Ministry of Health (MOH) recommendations. METHODS: An observational multicenter, cross-sectional survey study was conducted from February 1, 2021 to June 30, 2021 in five cities in Peru. Two surveys were conducted to assess knowledge, attitudes, and practices concerning maternal immunization: one among pregnant/postpartum women and one among HCPs. RESULTS: Participants were 668 pregnant/postpartum women with a mean age of 29.6 years and 219 HCPs-mostly midwives (46.6%) and obstetricians/gynecologists (44.7%). Of the pregnant/postpartum women, 66.9% knew that, in general, vaccinations are given for prevention, and 98.5% believed vaccines are important. Nonetheless, 69.6% of pregnant/postpartum women had poor or moderate knowledge of maternal vaccination. Disease knowledge of influenza (89.1%) and tetanus (87.0%) was high, while knowledge of pertussis (37.7%) was low. Women agreed/strongly agreed that they would get vaccinated with Tdap if a doctor (96.3%), midwife (88.9%), or nurse (72.0%) recommended it. Of the HCPs, 81.3% routinely recommended Tdap vaccination for pregnant women. CONCLUSIONS: To enhance vaccine acceptance in pregnant women in Peru, we must improve knowledge of the diseases, MOH recommendations, and benefits of the offered vaccinations. HCPs could provide this vaccination knowledge and information along with their vaccination recommendation as the pregnant/postpartum women indicated they would take the vaccines if recommended by their HCPs. Our findings are important for the successful implementation of maternal immunization programs in Peru.

Colonizing and Virulence Factors in Enterotoxigenic Escherichia coli from Peru.

Enterotoxigenic Escherichia coli (ETEC) ranks among the most relevant diarrheagenic pathogens. Efforts to design vaccines to fight ETEC have been focused on colonizing factors (CFs) and atypical virulence factors (AVF). An effective vaccine must account for differences in the regional prevalence of these CFs and AVFs to be truly effective in a given area. In the present study, the presence of 16 CFs and 9 AVFs, as well as the heat-stable (ST) variants (STh or STp), was established by polymerase chain reaction in 205 Peruvian ETEC isolates (120 from diarrhea cases and 85 from healthy controls). Ninety-nine (48.3%) isolates were heat-labile, 63 (30.7%) ST, and 43 (21.0%) presented both toxins. Of ST isolates, 59 (28.8%) possessed STh, 30 (14.6%) STp, five (2.4%) both STh and STp, and 12 (5.8%) were not amplified for any variant tested. The presence of CFs was associated with diarrhea (P < 0.0001). The presence of eatA as well as concomitant presence of CSI, CS3, and CS21 and of C5 and C6 was statistically related to diarrhea cases. The present results suggests that, if effective, a vaccine considering CS6, CS20, and CS21, together with EtpA, would provide protection against 64.4% of the isolates analyzed, whereas the addition of CS12 and EAST1 would lead to 83.9% coverage. Large studies are needed to establish both the ideal candidates to be considered to develop a vaccine effective in the area, and continuous surveillance is needed to detect displacement of circulating isolates that may compromise future vaccines.

Extra-genital Neisseria gonorrhoeae infections with genetic mutations conferring ciprofloxacin resistance among men who have sex with men and transgender women in Lima, Peru.

BACKGROUND: The increasing prevalence of drug-resistant Neisseria gonorrhoeae (NG) infections has caused great concern. Ciprofloxacin remains the empiric antimicrobial recommended to treat NG infections in Peru disregarding the susceptibility profile of circulating NG strains. We report the prevalence of individuals infected with NG strains presenting mutations in the gyrA gene that confers ciprofloxacin resistance. METHODS: We conducted a descriptive study assessing extragenital swab samples collected from a cohort of men who have sex with men and transgender women in Lima, Peru. Anal and pharyngeal NG positive swabs for Aptima Combo 2 assay (Hologic Inc., USA) were used for DNA extraction. We performed TaqMan real time PCR assays to detect a point mutation at codon Ser91 of the gyrase A (gyrA) gene. RESULTS: From 156 individuals who had at least one positive sample for NG reported by the Aptima assay, 80 individuals had at least one amplified DNA for the gyrA gene. We found that 67 of them (84.0%) were infected with a gyrA-mutated NG strain at the Ser91 codon. CONCLUSIONS: We report a high prevalence of gyrA mutation conferring ciprofloxacin resistance among individuals with extragenital NG infection. Empirical treatment of NG needs to be urgently updated in Peru in concordance with international guidelines.

Bovine lactoferrin for the prevention of COVID-19 infection in health care personnel: a double-blinded randomized clinical trial (LF-COVID).

Lactoferrin (LF) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to determine the effect of bovine lactoferrin (bLF) in the prevention of SARS-CoV-2 infection in health care personnel. A randomized, double-blinded, placebo-controlled clinical trial was conducted in two tertiary hospitals that provide care to patients with SARS-CoV-2 infection in Lima, Peru. Daily supplementation with 600 mg of enteral bLF versus placebo for 90 days was compared. Participants were weekly screened for symptoms suggestive of SARS-CoV-2 infection and molecular testing was performed on suspected episodes. A serological test was obtained from all participants at the end of the intervention. The main outcome included symptomatic and asymptomatic cases. A sub-analysis explored the time to symptomatic infection. Secondary outcomes were the severity, frequency, and duration of symptomatic infection. The study was prematurely cancelled due to the availability of vaccines against SARS-CoV-2 in Peru. 209 participants were enrolled and randomized, 104 received bLF and 105 placebo. SARS-CoV-2 infection occurred in 11 (10.6%) participants assigned to bLF and in 9 (8.6%) participants assigned to placebo without significant differences (Incidence Rate Ratio = 1.23, 95%CI 0.51-3.06, p-value = 0.64). There was no significant effect of bLF on time to symptomatic infection (Hazard Ratio = 1.61, 95%CI 0.62-4.19, p-value = 0.3). There were no significant differences in secondary outcomes. A significant effect of bLF in preventing SARS-CoV-2 infection was not proven. Further studies are needed to assess the effect of bLF supplementation on SARS-CoV-2 infection.Clinical trial registration ClinicalTrials.gov Identifier: NCT04526821, https://clinicaltrials.gov/ct2/show/NCT04526821?term=LACTOFERRIN&cond=COVID-19&cntry=PE&city=Lima&draw=2&rank=1 .

Class 1 and 2 Integrons in Escherichia coli Strains Isolated from Diarrhea and Bacteremia in Children Less Than 2 Years of Age from Peru.

Class 1 and Class 2 integrons are mobilizable elements able to carry a variety of antibiotic resistance determinants. In the present study, Class 1 and 2 integrons present in 355 pathogenic Escherichia coli (285 diarrheagenic, of these 129 were enteropathogenic, 90 enteroaggregative, 66 enterotoxigenic, and 70 bacteremic) isolated from healthy and ill children under age 5 from periurban areas of Lima, Peru, were characterized. The presence of integrase 1 and 2 was established by polymerase chain reaction (PCR), and variable regions were grouped by PCR-restriction fragment length polymorphism and subsequent sequencing. Antimicrobial resistance was established by disk diffusion. Ninety-seven isolates (27.3%) presented integrase 1, and 16 (4.5%) presented integrase 2 (P < 0.0001); in addition, seven (2.0%) isolates, six diarrheagenic and one bacteremic, presented both integrase genes. The presence of integrase 1 was more frequent among bacteremic isolates (P = 0.0004). Variable regions were amplified in 76/120 (63.3%) isolates with up to 14 gene arrangements. The most prevalent gene cassettes were those encoding dihydrofolate reductases as well as aminoglycoside modifying enzymes. Of note, Class 1 integrons tended to be associated with the presence of extended-spectrum ß-lactamases (ESBLs). A variety of Class 1 and 2 integrons were detected in diarrheagenic and bacteremic E. coli, demonstrating the heterogeneity of variable regions circulating in the area. The association of integrons with ESBLs is worrisome and has an impact on the development of multidrug resistance.

Increase of Macrolide-Resistance in Streptococcus pneumoniae Strains After the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in Lima, Peru.

Streptococcus pneumoniae upper respiratory infections and pneumonia are often treated with macrolides, but recently macrolide resistance is becoming an increasingly important problem. The 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the National Immunization Program of Peru in 2015. This study aimed to evaluate the temporal evolution of macrolide resistance in S. pneumoniae isolates collected in five cross-sectional studies conducted before and after this vaccine introduction, from 2006 to 2019 in Lima, Peru. A total of 521 and 242 S. pneumoniae isolates recovered from nasopharyngeal swabs from healthy carrier children < 2 years old (2 carriage studies) and samples from normally sterile body areas from pediatric patients with invasive pneumococcal disease (IPD) (3 IPD studies), respectively, were included in this study. Phenotypic macrolide resistance was detected using the Kirby-Bauer method and/or MIC test. We found a significant increase in macrolide resistance over time, from 33.5% to 50.0% in carriage studies, and from 24.8% to 37.5% and 70.8% in IPD studies. Macrolide resistance genes [erm(B) and mef(A/E)] were screened using PCR. In carriage studies, we detected a significant decrease in the frequency of mef(A/E) genes among macrolide-resistant S. pneumoniae strains (from 66.7% to 50.0%) after introduction of PCV13. The most common mechanism of macrolide-resistant among IPD strains was the presence of erm(B) (96.0%, 95.2% and 85.1% in the 3 IPD studies respectively). Macrolide resistance was more common in serotype 19A strains (80% and 90% among carriage and IPD strains, respectively) vs. non-serotype 19A (35.5% and 34.4% among carriage and IPD strains, respectively). In conclusion, S. pneumoniae macrolide resistance rates are very high among Peruvian children. Future studies are needed in order to evaluate macrolide resistance trends among pneumococcal strains, especially now after the COVID-19 pandemic, since azithromycin was vastly used as empiric treatment of COVID-19 in Peru.

A Streptococcus pneumoniae lineage usually associated with pneumococcal conjugate vaccine (PCV) serotypes is the most common cause of serotype 35B invasive disease in South Africa, following routine use of PCV.

Pneumococcal serotype 35B is an important non-conjugate vaccine (non-PCV) serotype. Its continued emergence, post-PCV7 in the USA, was associated with expansion of a pre-existing 35B clone (clonal complex [CC] 558) along with post-PCV13 emergence of a non-35B clone previously associated with PCV serotypes (CC156). This study describes lineages circulating among 35B isolates in South Africa before and after PCV introduction. We also compared 35B isolates belonging to a predominant 35B lineage in South Africa (GPSC5), with isolates belonging to the same lineage in other parts of the world. Serotype 35B isolates that caused invasive pneumococcal disease in South Africa in 2005-2014 were characterized by whole-genome sequencing (WGS). Multi-locus sequence types and global pneumococcal sequence clusters (GPSCs) were derived from WGS data of 63 35B isolates obtained in 2005-2014. A total of 262 isolates that belong to GPSC5 (115 isolates from South Africa and 147 from other countries) that were sequenced as part of the global pneumococcal sequencing (GPS) project were included for comparison. Serotype 35B isolates from South Africa were differentiated into seven GPSCs and GPSC5 was most common (49 %, 31/63). While 35B was the most common serotype among GPSC5/CC172 isolates in South Africa during the PCV13 period (66 %, 29/44), 23F was the most common serotype during both the pre-PCV (80 %, 37/46) and PCV7 period (32 %, 8/25). Serotype 35B represented 15 % (40/262) of GPSC5 isolates within the global GPS database and 75 % (31/40) were from South Africa. The predominance of the GPSC5 lineage within non-vaccine serotype 35B, is possibly unique to South Africa and warrants further molecular surveillance of pneumococci.

Clinical Course of Children with Campylobacter Gastroenteritis With and Without Co-Infection in Lima, Peru.

This study describes the clinical course of gastroenteritis caused by Campylobacter spp. as a single-infection versus coinfection and the corresponding changes that occur according to the treatment received, in children between 12 and 24 months of age. This descriptive study is based on the data of a pediatric cohort conducted between 2008 and 2011 of 555 children in Lima, Peru. Ninety-six diarrheal episodes with positive cultures for Campylobacter spp. were evaluated. In 52 episodes, empirical antibiotic treatment was started before pathogen isolation. Of these 96 episodes, 64.6% were coinfections with other pathogens. Coinfections were led by Escherichia coli, norovirus, and Giardia. Compared with single-infection episodes, coinfections had a mean symptom duration of 6.6 versus 5.7 days, a mean frequency of bowel movements per episode of 18.9 versus 14.8, and occurrence of vomiting and fever in 24.2% versus 14.7% of patients. Most of the patients with more severe clinical features at diagnosis were prescribed macrolides as empiric treatment. In the single-infection group, symptom duration was 7.2 ± 3.3 days in the macrolide-treated group and 7.9 ± 2.7 days in the nonmacrolide group. Diarrhea caused by coinfection appeared to be generally more severe than a single-pathogen. Patients with more severe clinical courses who received macrolides treatment might have had a faster recovery than patients who received nonmacrolides.

Knowledge, attitudes and practices of parents towards antibiotic use in rural communities in Peru: a cross-sectional multicentre study.

BACKGROUND: The inappropriate use of antibiotics significantly contributes to the development of antibiotic resistance. There is limited information about the use of antibiotics among parents from rural areas in Peru. This study aimed to describe the knowledge, attitudes and practices towards antibiotics among parents of children < 5 years of age from rural communities in Peru; to explore the association between knowledge and attitudes towards antibiotics and to explore determinants of low knowledge and self-medicating his/her child with antibiotics. METHODS: Cross-sectional study in six rural primary health centres in Peru using a self-administered survey. Crude and adjusted Prevalence Ratios (PR), and 95% Confidence Intervals (95% CI) were calculated to explore determinants of low knowledge and of having self-medicated his/her child with antibiotics. Linear regression was used to explore the association between knowledge and attitudes. RESULTS: A total of 231 parents were included. The largest gap in knowledge was among 183 parents (79%) who did not know that antibiotics cannot cure viral infections. The largest gap in attitudes was among 185 participants (80%) that did not disagree with "If I want my child to receive antibiotics, I would not be satisfied if the doctor refuses to prescribe them". More than half of parents (n = 120, 52%) reported having self-medicated his/her child with antibiotics. A positive correlation was found between knowledge and attitudes (Coefficient 0.53, 95% CI 0.38-0.68) after adjusting for the age and the education of the parent. Parents who were < 20 years old were more likely to have low knowledge about antibiotics (crude PR 2.39, 95% CI 1.32-4.34) compared to those aged > 40 years. Parents who had self-medicated his/her child with antibiotics (n = 120, 52%) were more likely to have purchased antibiotics without prescription (aPR 2.70, 95% CI 1.74-4.19) and to have received antibiotics after the recommendation of a pharmacist (aPR 1.79, 95% CI 1.13-2.82). CONCLUSIONS: Knowledge about antibiotics among parents from rural settings in Peru is limited and highlights the need for educational interventions. Public health policies to limit the acquisition of antibiotics without prescription should be implemented.

High Prevalence of blaCTX-M in Fecal Commensal Escherichia coli from Healthy Children.

BACKGROUND: Antibiotic-resistant Escherichia coli can colonize the intestinal tract of healthy children, causing concern when antibiotic resistance is related to the presence of transferable mechanisms, such as extended-spectrum ß-lactamases (ESBLs). MATERIALS AND METHODS: Fecal samples from 41 healthy children from two villages of rural Peru were cultured on ceftriaxone-disks. ESBL production was confirmed with double disk synergy. In all ESBL-produced isolates, antibiotic susceptibility to 12 antibacterial agents was established by disk diffusion, while clonal relationships were determined by repetitive extragenic palindromic-polymerase chain reaction (REP-PCR). Presence of ST131 was determined using PCR. RESULTS: Ceftriaxone-resistant microorganisms were recovered from 39 samples belonging to 22 out of 41 children (53.7%). Of these, 80 ceftriaxone-resistant and two ceftriaxone-intermediate E. coli from inside ceftriaxone-halos were confirmed as ESBL-producers. All isolates were multidrug-resistant. In 79/80 (98.8%) ceftriaxone-resistant isolates, the presence of blaCTX-M was detected alone (58 isolates, or together with other ß-lactamase (blaTEM, 17 isolates; blaOXA-1-like, 3 isolates; blaTEM + blaOXA-1-like, 1 isolate), while in one isolate no such ESBL was identified. The two ceftriaxone-intermediate isolates recovered from the same sample, carried a blaTEM and blaSHV respectively. Thirty-four different clones were identified, with 4 clones being recovered from different samples from the same child. Twelve clones were disseminated among different children, including 5 clones disseminated between both villages. Two clones, accounting for 3 isolates and both recovered from the same children, belonged to E. coli ST131. CONCLUSION: This study demonstrates high prevalence of ESBL-carriers among healthy children living in a rural area of Peru, stressing the need for continuous surveillance and search for public health control measures.

Pneumocystis primary infection in non-immunosuppressed infants in Lima, Peru.

OBJECTIVES: To provide original data on Pneumocystis primary infection in non-immunosuppressed infants from Peru. METHODS: A cross sectional study was performed. Infants less than seven months old, without any underlying medical conditions attending the "well baby" outpatient clinic at one hospital in Lima, Peru were prospectively enrolled during a 15-month period from November 2016 to February 2018. All had a nasopharyngeal aspirate (NPA) for detection of P. jirovecii DNA using a PCR assay, regardless of respiratory symptoms. P. jirovecii DNA detection was considered to represent pulmonary colonization contemporaneous with Pneumocystis primary infection. Associations between infants' clinical and demographic characteristics and results of P. jirovecii DNA detection were analyzed. RESULTS: P. jirovecii DNA was detected in 45 of 146 infants (30.8%) and detection was not associated with concurrent respiratory symptoms in 40 of 45 infants. Infants with P. jirovecii had a lower mean age when compared to infants not colonized (p <0.05). The highest frequency of P. jirovecii was observed in 2-3-month-old infants (p < 0.01) and in the cooler winter and spring seasons (p <0.01). Multivariable analysis showed that infants living in a home with ≤ 1 bedroom were more likely to be colonized; Odds Ratio =3.03 (95%CI 1.31-7.00; p = 0.01). CONCLUSION: Pneumocystis primary infection in this single site in Lima, Peru, was most frequently observed in 2-3-month-old infants, in winter and spring seasons, and with higher detection rates being associated with household conditions favoring close inter-individual contacts and potential transmission of P. jirovecii.

COVID-19 vaccine equity: a health systems and policy perspective.

INTRODUCTION: The global COVID-19 vaccine rollout has highlighted inequities in the accessibility of countries to COVID-19 vaccines. Populations in low- and middle-income countries have found it difficult to have access to COVID-19 vaccines. AREAS COVERED: This perspective provides analyses on historical and contemporary policy trends of vaccine development and immunization programs, including the current COVID-19 vaccination drive, and governance challenges. Moreover, we also provide a comparative health system analysis of the COVID-19 vaccine deployment in some countries from different continents. It recommends that the international Access to COVID-19 Tools Accelerator (ACT-A) partnership requires a strong governance mechanism and urgent financial investment. EXPERT OPINION: All WHO member states should agree on technology transfer and voluntary license-sharing via a commonly governed technology access pool and supported by a just Intellectual Property regime. Contextualized, dynamic understandings and country-specific versions of health systems strengthening are needed to improve vaccine equity in a sustainable matter.

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial.

BACKGROUND: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate. METHODS: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 µg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing. FINDINGS: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group. INTERPRETATION: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates. FUNDING: German Federal Ministry of Education and Research and CureVac.

Acute Gastroenteritis Morbidity and Mortality Trends Following Universal Rotavirus Vaccination in Children in Peru: Ecological Database Study with Time-Trend Analysis.

INTRODUCTION: Rotavirus (RV) infection is the leading cause of severe diarrhea in children worldwide. It is responsible for around 25% of gastroenteritis (GE) cases, 33% of hospitalized GE cases, and an annual mortality rate of 113.4/100,000 in children < 5 years of age in Peru. RV infant vaccination is recommended by the World Health Organization and provides the best public health strategy to manage the disease. Universal RV vaccination was introduced in Peru in 2009. METHODS: Trends in GE ambulatory visits, hospitalizations, and deaths in children < 5 years of age are described in the pre-vaccination (2004-2008) versus post-vaccination (2010-2018) periods. Time-trend analysis was performed (using generalized linear regression models) to assess the impact of vaccination nationwide and by region after adjusting for variables. RESULTS: Between 2009 and 2011, vaccination coverage increased to over 80% in Peru. In infants < 1 year of age, GE ambulatory cases, hospitalizations, and deaths decreased in the post-vaccination period by 40.3%, 46.2%, and 55.5%, respectively (and in children < 5 years of age, by 34.4%, 41.9%, and 54.3%, respectively) compared with the pre-vaccination period. Results of the multivariate time-trend analysis also found significant decreases in the post-vaccination period of 10.7% (GE ambulatory cases), 17.2% (GE hospitalizations), and 37.3% (GE mortality) in children < 5 years of age. Data analyzed by region varied, with Costa and Sierra regions generally in line with the national findings; however, some findings were less robust for Selva due to fewer available data. CONCLUSION: After 9 years of RV vaccination in Peru, there appears to be a statistically significant positive impact of vaccination, in terms of reducing GE-related mortality, hospitalizations, and ambulatory visits in infants and young children. For policymakers to understand regional differences and future vaccination needs, continued improvement in surveillance is needed.

Characterization of Escherichia coli D7111 producing the ß-LACTAMASE TEM-176. / Caracterización de Escherichia coli D7111 productora de ß-LACTAMASA TEM-176.

The present report is the original description of bla TEM-176. The mechanisms of resistance to antimicrobial agents were determined in an enterotoxigenic Escherichia coli, determining the susceptibility to 22 antimicrobials classified in 15 different groups by agar diffusion and establishing the phylogenetic group, mechanisms of resistance and presence of Class 1 and 2 integrons. Integrons and ß-lactam resistance genes were sequenced. The isolate, belonging to phylogenetic group A, showed the presence of resistance or diminished susceptibility to a ampicillin, amoxicillin plus clavulanic acid, nalidíxic acid, ciprofloxacin, streptomycin, kanamycin, tetracycline, trimethoprim, sulfisoxazole, cotrimoxazole, azithromycin and nitrofurantoin, carrying bla TEM, aadA1/2, aphA1, sul3, tet(A) and a Class 2 integron containing a dfrA1 gene. Quinolone resistance was related to the substitution Ser83Ala. The TEM sequencing showed the presence of the new substitution Ala222Val, which led to the description of the new ß-lactamase bla TEM-176.

El presente reporte es la descripción original de bla TEM-176. Se caracterizaron los mecanismos de resistencia a antimicrobianos de un aislamiento de Escherichia coli enterotoxigénica, determinándose la resistencia a 22 antimicrobianos categorizados en 15 grupos diferentes mediante difusión en agar, estableciéndose grupo filogenético, mecanismos de resistencia y presencia de integrones de Clase 1 y 2 mediante PCR. Integrones y genes de resistencia a ß-lactámicos fueron secuenciados. El aislamiento del grupo filogenético A, mostró resistencia o sensibilidad disminuida a ampicilina, amoxicilina más ácido clavulánico, ácido nalidíxico, ciprofloxacino, estreptomicina, kanamicina, tetraciclina, trimetoprim, sulfisoxazol, cotrimoxazol, azitromicina y nitrofurantoina, detectándose la presencia de bla TEM, aadA1/2, aphA1, sul3, tet(A) y un integron de Clase 2 conteniendo un gen dfrA1. La resistencia a quinolonas se relacionó con la substitución Ser83Ala. La secuencia de TEM mostró la substitución Ala222Val, la cual a la fecha no había sido descrita, reportándose como una nueva ß-lactamasa, con el nombre de bla TEM-176.