Serosurvey of human antibodies recognizing Aedes aegypti D7 salivary proteins in Colombia

Citation: Londono-Renteria, B. L., Shakeri, H., Rozo-Lopez, P., Conway, M. J., Duggan, N., Jaberi-Douraki, M., & Colpitts, T. M. (2018). Serosurvey of Human Antibodies Recognizing Aedes aegypti D7 Salivary Proteins in Colombia. Frontiers in Public Health, 6. https://doi.org/10.3389/fpubh.2018.00111Background: Dengue is one of the most geographically significant mosquito-borne viral diseases transmitted by Aedes mosquitoes. During blood feeding, the mosquito deposits salivary proteins that induce antibody responses. These can be related to the intensity of exposure to bites. Some mosquito salivary proteins, such as D7 proteins, are known as potent allergens. The antibody response to D7 proteins can be used as a marker to evaluate the risk of exposure and disease transmission, and provide critical information for understanding the dynamics of vector-host interactions. Methods: The study was conducted at the Los Patios Hospital, Cucuta, Norte de Santander, Colombia. A total of 63 participants were enrolled in the study. Participants were categorized into three disease status groups, age groups, and socioeconomic strata. The level of IgG antibodies against D7 Aedes proteins was determined by ELISA. We used a statistical approach to determine if there is an association between antibody levels and factors such as age, living conditions, and dengue virus infection. Results: We found that IgG antibodies against D7 proteins were higher in non-DENV infected individuals in comparison to DENV-infected participants. Also, age factor showed a significant positive correlation with IgG antibodies against D7 proteins, and the living conditions (socioeconomic stratification), in people ages 20 years or older, are a statistically significant factor in the variability of IgG antibodies against D7 proteins. Conclusions: This pilot study represents the first approximation to elucidate any correlation between the antibody response against mosquito D7 salivary proteins and its correlation with age, living conditions and dengue virus infection in a dengue endemic area

Oral rehydration versus intravenous therapy for treating dehydration due to gastroenteritis in children: a meta-analysis of randomised controlled trials

BACKGROUND: Despite treatment recommendations from various organizations, oral rehydration therapy (ORT) continues to be underused, particularly by physicians in high-income countries. We conducted a systematic review of randomised controlled trials (RCTs) to compare ORT and intravenous therapy (IVT) for the treatment of dehydration secondary to acute gastroenteritis in children. METHODS: RCTs were identified through MEDLINE, EMBASE, CENTRAL, authors and references of included trials, pharmaceutical companies, and relevant organizations. Screening and inclusion were performed independently by two reviewers in order to identify randomised or quasi-randomised controlled trials comparing ORT and IVT in children with acute diarrhea and dehydration. Two reviewers independently assessed study quality using the Jadad scale and allocation concealment. Data were extracted by one reviewer and checked by a second. The primary outcome measure was failure of rehydration. We analyzed data using standard meta-analytic techniques. RESULTS: The quality of the 14 included trials ranged from 0 to 3 (Jadad score); allocation concealment was unclear in all but one study. Using a random effects model, there was no significant difference in treatment failures (risk difference [RD] 3%; 95% confidence intervals [CI]: 0, 6). The Mantel-Haenzsel fixed effects model gave a significant difference between treatment groups (RD 4%; 95% CI: 2, 5) favoring IVT. Based on the four studies that reported deaths, there were six in the IVT groups and two in ORT. There were no significant differences in total fluid intake at six and 24 hours, weight gain, duration of diarrhea, or hypo/hypernatremia. Length of stay was significantly shorter for the ORT group (weighted mean difference [WMD] -1.2 days; 95% CI: -2.4,-0.02). Phlebitis occurred significantly more often with IVT (number needed to treat [NNT] 33; 95% CI: 25,100); paralytic ileus occurred more often with ORT (NNT 33; 95% CI: 20,100). These results may not be generalizable to children with persistent vomiting. CONCLUSION: There were no clinically important differences between ORT and IVT in terms of efficacy and safety. For every 25 children (95% CI: 20, 50) treated with ORT, one would fail and require IVT. The results support existing practice guidelines recommending ORT as the first course of treatment in appropriate children with dehydration secondary to gastroenteritis

Which resources should be used to identify RCT/CCTs for systematic reviews: a systematic review

BACKGROUND: Systematic reviewers seek to comprehensively search for relevant studies and summarize these to present the most valid estimate of intervention effectiveness. The more resources searched, the higher the yield, and thus time and costs required to conduct a systematic review. While there is an abundance of evidence to suggest how extensive a search for randomized controlled trials (RCTs) should be, it is neither conclusive nor consistent. This systematic review was conducted in order to assess the value of different resources to identify trials for inclusion in systematic reviews. METHODS: Seven electronic databases, four journals and Cochrane Colloquia were searched. Key authors were contacted and references of relevant articles screened. Included studies compared two or more sources to find RCTs or controlled clinical trials (CCTs). A checklist was developed and applied to assess quality of reporting. Data were extracted by one reviewer and checked by a second. Medians and ranges for precision and recall were calculated; results were grouped by comparison. Meta-analysis was not performed due to large heterogeneity. Subgroup analyses were conducted for: search strategy (Cochrane, Simple, Complex, Index), expertise of the searcher (Cochrane, librarian, non-librarian), and study design (RCT and CCT). RESULTS: Sixty-four studies representing 13 electronic databases met inclusion criteria. The most common comparisons were MEDLINE vs. handsearching (n = 23), MEDLINE vs. MEDLINE+handsearching (n = 13), and MEDLINE vs. reference standard (n = 13). Quality was low, particularly for the reporting of study selection methodology. Overall, recall and precision varied substantially by comparison and ranged from 0 to 100% and 0 to 99%, respectively. The trial registries performed the best with median recall of 89% (range 84, 95) and median precision of 96.5% (96, 97), although these results are based on a small number of studies. Inadequate or inappropriate indexing was the reason most cited for missing studies. Complex and Cochrane search strategies (SS) performed better than Simple SS. CONCLUSION: Multiple-source comprehensive searches are necessary to identify all RCTs for a systematic review, although indexing needs to be improved. Although trial registries demonstrated the highest recall and precision, the Cochrane SS or a Complex SS in consultation with a librarian are recommended. Continued efforts to develop CENTRAL should be supported

Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

Monoclonal Antibodies for the Treatment and Prevention of AIDS Virus Infection

Nearly 40 years after the discovery of HIV and the AIDS pandemic, there is still no effective vaccine or cure. Recent efforts have focused on the isolation and use of potent broadly neutralizing antibodies (bNAbs) for the treatment and prevention of HIV. The non-human primate (NHP) model is essential in the development of new therapeutics and prevention strategies against HIV. Studies conducted in humans as well as SIV and SHIV-infected rhesus macaques have shown potent anti-viral protection of human bNAbs delivered via passive transfer. However, passive delivery of antibodies is limited in terms of applicability on a global scale. The use of adeno-associated virus (AAV) as a vector for the delivery of bNAbs is a promising approach for the long-term expression of antibodies. The dissertation enclosed herein addresses two projects. Firstly, a technique to improve isolation of bNAbs, and secondly, the use AAV as a vector to deliver bNAbs to SHIV-infected monkeys to mediate virologic suppression.BG505 SOSIP.664, a stabilized trimeric mimic of the HIV-1 envelope spike, has been a useful tool for isolating anti-HIV-1 neutralizing antibodies. However, the SOSIP trimer can isolate non-neutralizing antibodies as well, many of which are gp41-specific. We set forth to decrease the amount of gp41 SOSIP-base-specific monoclonal antibodies (mAbs) isolated. We accomplished this by introducing a blocking step with gp41 recombinant protein. We found a significantly higher proportion of mAbs with neutralizing activity were obtained with this new strategy.In addition, we conducted a therapy trial where long-term SHIV-AD8 infected macaques received AAV-encoded mAbs 3BNC117, 10-1074, and 10E8. A strong anti-drug antibody (ADA) response restricting mAb delivery, but one animal (rh2438) successfully maintained 50-150 μg/ml of 3BNC117 and 10-1074 for six years. The delivery of these two mAbs resulted in an abrupt decline in plasma viremia to undetectable levels and a decline in anti-p27 and gp120 antibodies. Our results provide proof of concept for AAV-delivered mAbs producing a functional cure

SOSIP Trimer-Specific Antibodies Isolated from a Simian-Human Immunodeficiency Virus-Infected Monkey with versus without a Pre-blocking Step with gp41

BG505 SOSIP.664 (hereafter referred to as SOSIP), a stabilized trimeric mimic of the HIV-1 envelope spike resembling the native viral spike, is a useful tool for isolating anti-HIV-1 neutralizing antibodies. We screened long-term SHIV-AD8 infected rhesus monkeys for potency and breadth of serum neutralizing activity against autologous and heterologous viruses: SHIV-AD8, HIV-1 YU2, HIV-1 JR-CSF, and HIV-1 NL4-3. Monkey rh2436 neutralized all viruses tested and showed strong reactivity to the SOSIP trimer, suggesting this was a promising candidate for attempts at monoclonal antibody (MAb) isolation. MAbs were isolated by performing single B-cell sorts from peripheral blood mononuclear cells (PBMC) by FACS using the SOSIP trimer as a probe. An initial round of sorted cells revealed the majority of isolated MAbs were directed to the gp41 external domain portion of the SOSIP trimer and were mostly non-neutralizing against tested isolates. A second sort was performed, introducing a gp41 blocking step prior to PBMC staining and FACS sorting. These isolated MAbs bound SOSIP trimer but were no longer directed to the gp41 external domain portion. A significantly higher proportion of MAbs with neutralizing activity were obtained with this strategy. Our data show this pre-blocking step with gp41 greatly increases the yield of non-gp41-reactive, SOSIP-specific MAbs and increases the likelihood of isolating MAbs with neutralizing activity. Recent advancements in the field have focused on the isolation and use of broadly neutralizing antibodies for both prophylaxis and therapy. Finding a useful probe to isolate broad potent neutralizing antibodies while avoiding non-neutralizing antibodies is important. The SOSIP trimer has been shown to be a great tool for this purpose because it binds known broadly neutralizing antibodies. However, the SOSIP trimer can isolate non-neutralizing antibodies as well, including gp41-specific MAbs. Introducing a pre-blocking step with gp41 recombinant protein decreased the percent of gp41-specific antibodies isolated with SOSIP probe, as well as increased the number of neutralizing antibodies isolated. This method can be used as a tool to increase the chances of isolating neutralizing antibodies

Assessment of chemical and physical treatments to selectively kill non-indigenous freshwater zooplankton species

<p>Non-indigenous zooplankton species pose a biosecurity threat to New Zealand’s freshwater native taxa. Nine species are known to have established in New Zealand lakes to date. The spread of some zooplankton taxa is linked to the translocation of farmed fish, principally grass carp (<i>Ctenopharyngodon idella</i>), and recreational vessel movements. The aims of this study were to assess the effectiveness of a range of chemical and physical treatments for transport water and associated equipment to kill freshwater cladoceran, copepod, and rotifer zooplankton species, and their risk to non-target fish. Sodium chloride was the most effective and applicable chemical treatment tested at length in the cladoceran and, combined with physical treatment via mechanical filtration of water or hot water immersion of equipment (to also manage the risk of diapausing eggs), represents an effective option for the control of non-indigenous zooplankton, with limited impact on stenohaline fish.</p

Adeno-Associated Virus Delivery of Anti-HIV Monoclonal Antibodies Can Drive Long-Term Virologic Suppression

Long-term delivery of anti-HIV monoclonal antibodies (mAbs) using adeno-associated virus (AAV) vectors holds promise for the prevention and treatment of HIV infection. We describe a therapy trial in which four rhesus monkeys were infected with SHIV-AD8 for 86 weeks before receiving the AAV-encoded mAbs 3BNC117, 10-1074, and 10E8. Although anti-drug antibody (ADA) responses restricted mAb delivery, one monkey successfully maintained 50–150 μg/mL of 3BNC117 and 10-1074 for over 2 years. Delivery of these two mAbs to this monkey resulted in an abrupt decline in plasma viremia, which remained undetectable for 38 successive measurements over 3 years. We generated two more examples of virologic suppression using AAV delivery of a cocktail of four mAbs in a 12-monkey study. Our results provide proof of concept for AAV-delivered mAbs to produce a “functional cure.” However, they also serve as a warning that ADAs may be a problem for practical application of this approach in humans. [Display omitted] •Chronically SHIV-infected macaques were treated with AAV-delivered bnAbs•Long-term virologic suppression is possible with AAV-delivered antibodies•A functional cure was achieved in one SHIV-infected macaque•Development of host-generated anti-antibodies limited treatment effectiveness Although anti-retroviral drug therapy can suppress HIV viral replication, it is not a cure. Martinez-Navio et al. report the functional cure of the “Miami monkey,” in which long-term SHIV suppression was achieved after a single administration of adeno-associated viruses (AAVs) encoding broadly neutralizing antibodies. They also report that host-generated anti-antibodies can hamper the applicability of this approach