Envelope Deglycosylation Enhances Antigenicity of HIV-1 gp41 Epitopes for Both Broad Neutralizing Antibodies and Their Unmutated Ancestor Antibodies

The HIV-1 gp41 envelope (Env) membrane proximal external region (MPER) is an important vaccine target that in rare subjects can elicit neutralizing antibodies. One mechanism proposed for rarity of MPER neutralizing antibody generation is lack of reverted unmutated ancestor (putative naive B cell receptor) antibody reactivity with HIV-1 envelope. We have studied the effect of partial deglycosylation under non-denaturing (native) conditions on gp140 Env antigenicity for MPER neutralizing antibodies and their reverted unmutated ancestor antibodies. We found that native deglycosylation of clade B JRFL gp140 as well as group M consensus gp140 Env CON-S selectively increased the reactivity of Env with the broad neutralizing human mAbs, 2F5 and 4E10. Whereas fully glycosylated gp140 Env either did not bind (JRFL), or weakly bound (CON-S), 2F5 and 4E10 reverted unmutated ancestors, natively deglycosylated JRFL and CON-S gp140 Envs did bind well to these putative mimics of naive B cell receptors. These data predict that partially deglycoslated Env would bind better than fully glycosylated Env to gp41-specific naïve B cells with improved immunogenicity. In this regard, immunization of rhesus macaques demonstrated enhanced immunogenicity of the 2F5 MPER epitope on deglyosylated JRFL gp140 compared to glycosylated JRFL gp140. Thus, the lack of 2F5 and 4E10 reverted unmutated ancestor binding to gp140 Env may not always be due to lack of unmutated ancestor antibody reactivity with gp41 peptide epitopes, but rather, may be due to glycan interference of binding of unmutated ancestor antibodies of broad neutralizing mAb to Env gp41

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

Resistance of the predacious mite, euseius kenyae (acari: phytoseiidae) to chlorpyrifos (dursban ®) in kenyan coffee farms

This study was carried out to assess whether the predacious phytoseiid mite, Euseius kenyae (Swirski and Ragusa), commonly found in major  coffee growing regions in Kenya has developed resistance to Chlorpyrifos. Mite populations were collected from coffee farms harbouring E. kenyae and where Chlorpyrifos or other organophosphates were sprayed to manage the primary coffee insect pests. The mites collected were reared in mass in the laboratory for bioassays. The findings showed that under coffee agro-ecosystems, levels of resistance existed among the populations of E. kenyae after their exposure to Chlorpyrifos or other organophosphates. The population of E. kenyae from a coffee farm (C44) was most susceptible to Chlorpyrifos with LC50 = 0.044 that was below the lowest concentration of 0.1875 ml per litre of water which was tested. The E. kenyae from coffee farms (C1, C4, C7, C37, C25 and C119) had  resistance ratios more than ten times that of C44. The coffee farms (C2, C12, C19, C116, C31, C50 and C72) had populations of E. kenyae  susceptible to Chlorpyrifos at concentration of 0.75 ml per litre of water which is the field recommended rate for control of insect pests in coffee. The population of E. kenyae from C7 was resistant to the highest field rate of 200% (1.5 ml per litre of water) with LC50 of 1.716 and resistance ratio of 39 times. The existence of resistance populations of E. kenyae is an aspect that needs to be considered in the integrated pest control strategies against coffee insect pests

The incremental cost of delivering PrEP as a bridge to ART for HIV serodiscordant couples in public HIV care clinics in Kenya

Background. In 2016, the Kenyan Ministry of Health (MOH) released guidelines that recommend preexposure prophylaxis (PrEP) for persons with substantial ongoing HIV risk, including those in HIV serodiscordant partnerships. Estimates of the costs of delivering PrEP within Kenyan public health facilities are needed for planning for PrEP scale up. Methods. We estimated the incremental annual costs of providing PrEP to HIV uninfected partners as a time-limited “bridge” until the infected partner is virally suppressed on ART within HIV serodiscordant couples as part of routine clinic care in Thika, Kenya. Costs were collected from the Partners Demonstration Project, a prospective evaluation of integrated delivery of preexposure prophylaxis (PrEP) and antiretroviral therapy (ART) to high-risk HIV serodiscordant couples. We conducted time and motion studies to distinguish between activities related to research, routine clinical care, and PrEP delivery. Costs (2015 US dollars) were collected from the MOH perspective and divided into staff, transportation, equipment, supplies, buildings and overhead, and start-up. Results. PrEP related activities conducted during the screening, enrollment, and follow-up visits took an average of 13 minutes, 51 minutes, and 12 minutes, respectively. Assuming a staff structure of 3 counselors, 1 nurse, and 2 clinicians, we estimate that 3,178 couples can be screened, 1,444 couples offered PrEP and ART, and 6,138 couples followed up annually in an average HIV care clinic. Using costs incurred by the MOH for personnel, drug, and laboratory tests, we estimate that the incremental cost of offering PrEP to HIV uninfected partners within existing ART programs is $86.79 per couple per year. Personnel and PrEP medication made up the largest portion of the costs. We estimate that the total cost to Ministry of Health of delivering integrated PrEP and ART program in public health facilities is $250.19 per HIV serodiscordant couple per year. Conclusions. Time-limited provision of PrEP to the HIV uninfected partner within HIV serodiscordant couples can be an affordable delivery model implemented in HIV care programs in Kenya and similar settings. These costs can be used for budgetary planning and cost effectiveness analyses