Mateu Espasa

Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial

BACKGROUND Development of an effective malaria vaccine could greatly contribute to disease control. RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on Plasmodium falciparum circumsporozoite surface antigen. We aimed to assess vaccine efficacy, immunogenicity, and safety in young African children. METHODS We did a double-blind, phase IIb, randomised controlled trial in Mozambique in 2022 children aged 1-4 years. The study included two cohorts of children living in two separate areas which underwent different follow-up schemes. Participants were randomly allocated three doses of either RTS,S/AS02A candidate malaria vaccine or control vaccines. The primary endpoint, determined in cohort 1 (n=1605), was time to first clinical episode of P falciparum malaria (axillary temperature > or =37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) over a 6-month surveillance period. Efficacy for prevention of new infections was determined in cohort 2 (n=417). Analysis was per protocol. FINDINGS 115 children in cohort 1 and 50 in cohort 2 did not receive all three doses and were excluded from the per-protocol analysis. Vaccine efficacy for the first clinical episodes was 29.9% (95% CI 11.0-44.8; p=0.004). At the end of the 6-month observation period, prevalence of P falciparum infection was 37% lower in the RTS,S/AS02A group compared with the control group (11.9% vs 18.9%; p=0.0003). Vaccine efficacy for severe malaria was 57.7% (95% CI 16.2-80.6; p=0.019). In cohort 2, vaccine efficacy for extending time to first infection was 45.0% (31.4-55.9; p<0.0001). INTERPRETATION The RTS,S/AS02A vaccine was safe, well tolerated, and immunogenic. Our results show development of an effective vaccine against malaria is feasible.

Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial

BACKGROUND RTS,S/AS02A is a pre-erythrocytic stage malaria vaccine that provides partial protection against infection in malaria-naive adult volunteers and hyperimmune adults. A previous report showed that this vaccine reduced risk of clinical malaria, delayed time to new infection, and reduced episodes of severe malaria over 6 months in African children. An important remaining issue is the durability of protection against clinical disease in these children. METHODS We did a randomised, controlled, phase IIb trial of RTS,S/AS02A given at 0, 1, and 2 months in 2022 Mozambican children aged 1-4 years. We previously determined vaccine efficacy (VE) against clinical malaria in a double-blind phase that included study months 2.5-8.5 (VE(2.5-8.5)). We now report VE in a single-blind phase up to month 21 (VE(8.5-21)). The primary endpoint was time to first or only clinical episode of Plasmodium falciparum malaria (axillary temperature 37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) detected through a passive case detection system. We also determined VE for other case definitions and for episodes of severe malaria. This study is registered with the ClinicalTrials.gov identifier NCT00197041. FINDINGS During the single-blind phase, VE(8.5-21) was 28.9% (95% CI 8.4-44.8; p=0.008). At month 21, prevalence of P falciparum infection was 29% lower in the RTS,S/AS02A group than in the control (p=0.017). Considering the entire study period, VE(2.5-21) was 35.3% (95% CI 21.6-46.6; p<0.0001) and VE(2.5-21) for severe malaria was 48.6% (95% CI 12.3-71.0; p=0.02). INTERPRETATION These results show that RTS,S/AS02A confers partial protection in African children aged 1-4 years living in rural endemic areas against a range of clinical disease caused by P falciparum for at least 18 months, and confirm the potential of malaria vaccines to become credible control tools for public-health use.

Intermittent Preventive Treatment for Malaria Control Administered at the Time of Routine Vaccinations in Mozambican Infants: A Randomized, Placebo-Controlled Trial

BACKGROUND There is an urgent need to deploy and develop new control tools that will reduce the intolerable burden of malaria. Intermittent preventive treatment in infants (IPTi) has the potential to become an effective tool for malaria control. METHODS We performed a randomized, double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine (SP) treatment in 1503 Mozambican children. Doses of SP or placebo were given at 3, 4, and 9 months of age. The intervention was administered alongside routine vaccinations delivered through the Expanded Program on Immunization (EPI). Hematological and biochemical tests were done when infants were 5 months old. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys when infants were 12 and 24 months old. RESULTS IPTi was well tolerated, and no adverse events associated with SP were documented. During the first year of life, intermittent SP treatment reduced the incidence of clinical malaria by 22.2% (95% confidence interval [CI], 3.7%-37.0%; P=.020) and the rate of hospital admissions by 19% (95% CI, 4.0%-31.0%; P=.014). Although the incidence of severe anemia (packed cell volume of <25%) did not differ significantly between the 2 groups (protective effect, 12.7% [95% CI, -17.3% to 35.1%]; P=.36), there was a significant reduction in hospital admissions for anemia during the month after dosing for both the first and second dose. The serological responses to EPI vaccines were not modified by the intervention. CONCLUSIONS IPTi with SP has been shown to moderately reduce the incidence of clinical malaria in Mozambican infants without evidence of rebound after stopping the intervention or of interactions with EPI vaccines. Its recommendation as a malaria control strategy in Mozambique needs to be balanced against the scarcity of affordable control tools and the burden of malaria in children.

Emergence of OXA-48-producing Klebsiella pneumoniae and the novel carbapenemases OXA-244 and OXA-245 in Spain

OBJECTIVES To describe the molecular and population-level characterization of a selected group of OXA-48-like-producing Klebsiella pneumoniae isolates collected in Spain between January 2011 and May 2012. METHODS During the study period, 151 OXA-48-like-producing K. pneumoniae isolates were collected from 10 hospitals in six different Spanish regions. From these, a representative sample of 21 isolates that caused hospital outbreaks and single infections was selected for further in-depth analysis. Molecular epidemiology was investigated using PFGE and multilocus sequence typing (MLST). Resistance genes were characterized by PCR and sequencing. Plasmids carrying bla(OXA-48-like) were studied by PFGE with S1 nuclease digestion. RESULTS All 21 isolates had ertapenem MICs ≥ 1 mg/L, but 47.6% remained susceptible to imipenem and meropenem; bla(OXA-48) was identified in 19 isolates (90.5%) and the novel bla(OXA-244) and bla(OXA-245) genes were detected in 1 isolate each. With one exception, all isolates that contained bla(OXA-48-like) also contained bla(CTX-M-15). PFGE typing revealed six clusters comprising isolates that belonged to MLST types ST11, ST16, ST392, ST405, ST437 and ST663, respectively. Two main clusters were identified: PFGE cluster 1 (12 isolates, belonging either to ST405 or ST663, from seven hospitals), and PFGE cluster 2 (4 ST16 isolates from two hospitals). Six of seven donor isolates conjugated successfully; bla(OXA-48-like) (but not bla(CTX-M-15)) was carried on ≈ 60 kb Inc L/M plasmids. CONCLUSIONS Multidrug-resistant K. pneumoniae producing OXA-48-like carbapenemase are emerging as important pathogens in Spain due to intra- and inter-hospital, clonal and non-clonal dissemination.

Invasive pneumococcal disease in children <5 years of age in rural Mozambique

Objectives  To estimate the incidence and epidemiological characteristics of invasive pneumococcal disease (IPD) in children <5 years of age living in a rural area of southern Mozambique.

Trends in frequency and in vitro susceptibilities to antifungal agents, including voriconazole and anidulafungin, of Candida bloodstream isolates. results from a six-year study (1996–2001)

The frequency of isolation and antifungal susceptibility patterns to established and two new antifungal agents were determined for 218 Candida spp isolates causing bloodstream infection from 1996 to 2001. Overall, 41.7% of the candidemias were due to C. albicans, followed by C. parapsilosis (22%), C. tropicalis (16.1%), C. glabrata (11.9%), C. krusei (6%) and miscellaneous Candida spp (2.3%). Isolates of C. albicans C. parapsilosis and C. tropicalis (80% of isolates) were highly susceptible to fluconazole (94 to 100% at </= 8 microg/ml) and voriconazole (97 to 100% at </= 1 microg/ml). By comparison with the newer agents itraconazole was less active (77 to 97% at </=0.12 microg/ml). Only 77% and 15% of C. glabrata isolates were inhibited by fluconazole at </= 8 microg/ml and itraconazole at </=0.12 microg/ml, respectively. Voriconazole showed a remarkable in vitro potency against C. glabrata as well as C. krusei isolates (100% at </= 1 microg/ml). Anidulafungin was very active against Candida spp isolates (MIC90: </= 0.5 microg/ml), except C. parapsilosis (MIC90: 4 microg/ml) and two C. guilliermondii isolates (MIC: >/= 32 microg/ml).

Invasive non‐typhoidal Salmonella in Mozambican children

Objective  To describe the epidemiology and clinical presentation of invasive non‐typhoidal Salmonella (NTS) in Mozambique.

Antimicrobial Susceptibility and Mechanisms of Resistance in Shigella and Salmonella Isolates from Children under Five Years of Age with Diarrhea in Rural Mozambique

ABSTRACT The antimicrobial susceptibility and mechanisms of resistance of 109 Shigella and 40 Salmonella isolates from children with diarrhea in southern Mozambique were assessed. The susceptibility to seven antimicrobial agents was tested by disk diffusion, and mechanisms of resistance were searched by PCR or colorimetric method. A high proportion of Shigella isolates were resistant to chloramphenicol (Chl) (52%), ampicillin (Amp) (56%), tetracycline (Tet) (66%), and trimethoprim-sulfamethoxazole (Sxt) (84%). Sixty-five percent of the isolates were multidrug resistant. Shigella flexneri isolates were more resistant than those of Shigella sonnei to Amp (66% versus 0.0%, P < 0.001) and Chl (61% versus 0.0%, P < 0.001), whereas S. sonnei isolates presented higher resistance to Tet than S. flexneri isolates (93% versus 64%, P = 0.02). Resistance among Salmonella isolates was as follows: Tet and Chl, 15% each; Sxt, 18%; and Amp, 25%. Only 3% of Salmonella isolates were resistant to nalidixic acid (Nal), and none to ciprofloxacin or ceftriaxone (Cro). Among Salmonella isolates, multiresistance was found in 23%. Among Shigella isolates, antibiotic resistance was related mainly to the presence of oxa-1-like β-lactamases for Amp, dfrA1 genes for Sxt, tetB genes for Tet, and Chl acetyltransferase (CAT) activity for Chl. Among Salmonella isolates, resistance was conferred by tem-like β-lactamases for Amp, floR genes and CAT activity for Chl, tetA genes for Tet, and dfrA1 genes for Sxt. Our data show that Shigella isolates are resistant mostly to the most available, inexpensive antibiotics by various molecular mechanisms but remain susceptible to ciprofloxacin, Cro, and Nal, which is the first line for empirical treatment of shigellosis in the country.

Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique.

Background  The development of a malaria vaccine remains a public health priority for sub‐Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose‐escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine.

Haematological and biochemical indices in young African children: in search of reference intervals.

Introduction  The reference intervals of haematological and biochemical indices currently used in Africa are derived from data collected from populations living in industrialized countries. Few studies have been performed in Africa questioning the validity of these values when applied to local African populations.