Accelerating the development of a therapeutic vaccine for human Chagas disease: rationale and prospects.

Chagas disease is a leading cause of heart disease affecting approximately 10 million people in Latin America and elsewhere worldwide. The two major drugs available for the treatment of Chagas disease have limited efficacy in Trypanosoma cruzi-infected adults with indeterminate (patients who have seroconverted but do not yet show signs or symptoms) and determinate (patients who have both seroconverted and have clinical disease) status; they require prolonged treatment courses and are poorly tolerated and expensive. As an alternative to chemotherapy, an injectable therapeutic Chagas disease vaccine is under development to prevent or delay Chagasic cardiomyopathy in patients with indeterminate or determinate status. The bivalent vaccine will be comprised of two recombinant T. cruzi antigens, Tc24 and TSA-1, formulated on alum together with the Toll-like receptor 4 agonist, E6020. Proof-of-concept for the efficacy of these antigens was obtained in preclinical testing at the Autonomous University of Yucatan. Here the authors discuss the potential for a therapeutic Chagas vaccine as well as the progress made towards such a vaccine, and the authors articulate a roadmap for the development of the vaccine as planned by the nonprofit Sabin Vaccine Institute Product Development Partnership and Texas Children's Hospital Center for Vaccine Development in collaboration with an international consortium of academic and industrial partners in Mexico, Germany, Japan, and the USA.

Venom of Bothrops asper from Mexico and Costa Rica: intraspecific variation and cross-neutralization by antivenoms.

Bothrops asper is the species that induces the highest incidence of snakebite envenomation in southern Mexico, Central America and parts of northern South America. The intraspecies variability in HPLC profile and toxicological activities between the venoms from specimens collected in Mexico (Veracruz) and Costa Rica (Caribbean and Pacific populations) was investigated, as well as the cross-neutralization by antivenoms manufactured in these countries. Venoms differ in their HPLC profiles and in their toxicity, since venom from Mexican population showed higher lethal and defibrinogenating activities, whereas those from Costa Rica showed higher hemorrhagic and in vitro coagulant activities. In general, antivenoms were more effective in the neutralization of homologous venoms. Overall, both antivenoms effectively neutralized the various toxic effects of venoms from the two populations of B. asper. However, antivenom raised against venom from Costa Rican specimens showed a higher efficacy in the neutralization of defibrinogenating and coagulant activities, thus highlighting immunochemical differences in the toxins responsible for these effects associated with hemostatic disturbances in snakebite envenoming. These observations illustrate how intraspecies venom variation may influence antivenom neutralizing profile.

[Knowledge, attitudes and practices about influenza A(H1N1) 2009, and influenza vaccine in Mexico: results of a population survey]. / Conocimientos, actitudes y prácticas sobre la influenza A(H1N1) 2009 y la vacunación contra influenza pandémica: resultados de una encuesta poblacional.

OBJECTIVE: To assess knowledge, attitudes and practices regarding influenza pandemic, with special emphasis on issues related to influenza vaccine, seasonal and pandemic. MATERIALS AND METHODS: Cross-sectional study, probabilistic multistage sampling in patients over 18 years, residents of Mexico City (and metropolitan area), Monterrey, Guadalajara and Merida in December 2009. RESULTS: A total of 1.600 subjects (48.9% male) were interviewed, 34% had previously received seasonal flu vaccine, 90.6% were willing to be vaccinated against A(H1N1), 46.5% of those who would not receive the vaccine was because they did not trust A (H1N1), 68% considered influenza A (H1N1) as a risk for their family. Hand washing was the preventive measure most commonly reported (47.5%), secondly influenza vaccine (28%). Schooling (1.7, p=0.006) and age (1.02, p<0.001) influence rejection to get vaccine. 82.9% of respondents rate the federal government's management as good or very good. CONCLUSIONS: There was a high acceptance rate for the pandemic influenza vaccine in Mexico when compared to similar studies in other countries, the main reason for those who reject the vaccine was distrust in it.

Surveillance of nosocomial infections in a Mexican community hospital. How are we doing?

OBJECTIVE: To compare the nosocomial infection (NI) rate obtained from a retrospective review of clinical charts with that from the routine nosocomial infection surveillance system in a community hospital. MATERIAL AND METHODS: Retrospective review of a randomized sample of clinical charts.Results were compared to standard surveillance using crude and adjusted analyses. RESULTS: A total of 440 discharges were reviewed, there were 27 episodes of NIs among 22 patients. Cumulated incidence was 6.13 NI per 100 discharges. Diarrhea, pneumonia and peritonitis were the most common infections. Predictors of NI by Cox regression analysis included pleural catheter (HR 16.38), entry through the emergency ward, hospitalization in the intensive care unit (HR 7.19), and placement of orotracheal tube (HR 5.54). CONCLUSIONS: Frequency of NIs in this community hospital was high and underestimated. We identified urgent needs in the areas of training and monitoring.

Identification of seasonal vaccine hemagglutinin subtype 1 (H1) epitopes in Mexican isolates of the new influenza A (H1N1) 2009 virus.

BACKGROUND: Pre-existing immunity in individuals is a determinant condition for epidemic dynamics. During the current influenza A (H1N1) virus pandemic, cross-reactivity of seasonal vaccines from the last years and previous contact with seasonal influenza viruses was suggested as the cause of low severity and low incidence of the disease in persons aged 50-65 years and with history of seasonal influenza vaccination. METHODS: We performed a detailed search and analysis of 74 previously reported H1 epitopes present in influenza A virus contained in seasonal vaccines applied in Mexico from 2004 to date and in sequences from Mexican isolates from 2003, as well as in the recent influenza A (H1N1) 2009, and calculated the epitope conservation among vaccine, seasonal and pandemic influenza A (H1N1) virus. RESULTS: H1 epitope sequence identity ranged from 61.53-100 %. Of the 74 epitopes previously reported, 31 (41.9%) were completely conserved among all sequences analyzed in this study, whereas 43 (58.1%) had changes in one or more amino acids. CONCLUSIONS: Our findings contribute to the estimatation of the degree of epitope conservation among H1 from vaccine virus strains as well as in the different viruses that circulate in the Mexican population. These results may provide new elements to consider for analysis of cross-immunity to influenza viruses including the novel influenza A (H1N1) 2009 pandemic virus.

Vaccines against influenza A (H1N1) pandemic.

BACKGROUND AND AIMS: The World Health Organization (WHO) has reported, as of September 2009, that the influenza A (H1N1) influenza pandemic has originated >300,000 laboratory-confirmed cases and 3917 deaths in 191 countries. It is recognized that pandemic vaccines have their greatest impact as a preventive strategy when administered before or near the peak incidence of cases in an outbreak. Therefore, vaccination campaigns should be in place when influenza A (H1N1) 2009 vaccines are available. We undertook this study to provide updated information on clinical evaluation of influenza A (H1N1) vaccines and review recommendations for influenza A (H1N1) vaccination campaigns and public health policy. METHODS: The following methods were used: 1) review of registry at ClinicalTrials.gov. 2) search of PubMed Central (PMC) for influenza A (H1N1) vaccine. 3) review of recommendations of WHO, Mexican Health Secretariat (SSA) and Advisory Committee on Immunization Practices (ACIP) on influenza A (H1N1) vaccination campaigns. RESULTS: Until October 1, 2009 there were 11 available influenza A (H1N1) candidate strains provided by WHO Global Influenza Surveillance Network. ClinicalTrials.gov registers 45 phase I and II clinical trials evaluating immunogenicity and safety of influenza A (H1N1) vaccines. Preliminary results support administration of a single dose and use of adjuvants. Main recommendations of WHO, SSA and ACIP include epidemiologic considerations, objectives, definition of target groups and reinforcement of other mitigation measures. CONCLUSIONS: The present pandemic of influenza A (H1N1) has shown mild to moderate severity. Vaccination strategies in Mexico will have the objective of decreasing severe outcomes, slowing transmission, protecting groups at increased risk of infection, complications, or death, and preventing overload of health services. Control of the pandemic should include reinforcement of other non-pharmacologic measures of mitigation and, importantly, an adequate strategy of social communication.

Response of IFN-gamma and IgG to ESAT-6 and 38 kDa recombinant proteins and their peptides from Mycobacterium tuberculosis in tuberculosis patients and asymptomatic household contacts may indicate possible early-stage infection in the latter.

BACKGROUND: The ESAT-6 antigen from Mycobacterium tuberculosis evokes a protective immune response in murine models and is widely recognized by tuberculosis patients (TB) and healthy household contacts (HHC). However, little is known about human immune response to this antigen in populations from areas of high endemicity. This study aimed to determine the capacity of T-cells from a group of TB patients and HHC for cell proliferation and production of cytokines type Th1 or Th2 (IL-4, IL-10, and IFN-gamma) and to identify total IgG reactivity to the recombinant protein rESAT-6 and five overlapping synthetic peptides as well as to r38 kDa and two peptides. METHODS: T-cells from nine TB patients and nine HHC were stimulated with rESAT-6 and five overlapping synthetic peptides, previously selected from a set of 21 peptides and each of 16 amino acids in length (P1, P4, P6, P8, and P20). Similar experiments were carried out with r38 kDa and two peptides of 20 amino acids in length (38G and 38K). Cytokines in supernatants and total IgG from serum were determined by ELISA. RESULTS: Stimulation index (SI) was highest in HHC to rESAT-6 and peptides P1, P8, and P20. Differences in response to 38 kDa and 38G peptide between TB patients and HHC were not demonstrated. Cytokines from T-cell cultures were tested with a resulting SI=3.0. IFN-gamma was produced predominantly in HHC to rESAT-6, P8, and P20, while in TB patients production of IL-10 was detected in relation to r38 kDa. IL-4 was detected in minimal amounts in both groups. IgG from TB patients was predominantly recognized in connection with rESAT-6 and the P4 peptide, with an important response against r38 kDa detected in HHC. CONCLUSIONS: ESAT-6 recognition by HHC could indicate that these responses represent possible early-stage infections.

Inadequate therapy and antibiotic resistance. Risk factors for mortality in the intensive care unit.

BACKGROUND: The impact of nosocomial infections and multidrug resistance on mortality is a topic of considerable controversy. METHODS: A prospective, nested case control study was conducted in four intensive care units (ICUs) in Mexico to measure the impact of antibiotic resistance on and identify the main risk factors for mortality in critically ill patients with nosocomial infections. RESULTS: One hundred thirteen patients developed 119 nosocomial infections. Multivariate analysis identified two variables that were significantly and independently associated with mortality: ventilator-associated pneumonia (p = 0.0041, odds ratio [OR] = 7.7) and inadequate antibiotic treatment (p <0.0001, OR = 70.5). Although antibiotic resistance in Gram-negative rods was not an independent risk factor for mortality, there was a strong association between antibiotic resistance and inadequate treatment (chi2 for linear trend = 29.3, p <0.00001). For patients with ventilator-associated pneumonia, predicted mortality calculated by APACHE II score was 23% compared to an observed mortality of 71%. CONCLUSIONS: In this study the major risk factors for mortality were inadequate antibiotic treatment and development of ventilator-associated pneumonia. Multidrug resistance significantly increased the probability of receiving inadequate antibiotic treatment. The striking differences between observed and predicted mortality in these four ICUs indicate the need for further research and a reassessment of the current programs for prevention and control of nosocomial infections in Mexico.