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BackgroundAlternative approaches to syndromic management are needed to reduce rates of sexually transmitted infections (STIs) in resource-limited settings. We investigated the impact of point-of-care (POC) versus central laboratory–based testing on STI treatment initiation and STI adverse event (STI-AE) reporting.MethodsWe used Kaplan-Meier and Cox regression models to compare times to treatment initiation and STI-AE reporting among HVTN702 trial participants in South Africa. Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) were diagnosed POC at eThekwini clinic and in a central laboratory at Verulam/Isipingo clinics. All clinics used POC assays for Trichomonas vaginalis (TV) testing.ResultsAmong 959 women (median age, 23 [interquartile range, 21–26] years), median days (95% confidence interval [95%CI]) to NG/CT treatment initiation and NG/CT-AE reporting were 0.20 (.16–.25) and 0.24 (.19–.27) at eThekwini versus 14.22 (14.12–15.09) and 15.12 (13.22–21.24) at Verulam/Isipingo (all P < .001). Median days (95%CI) to TV treatment initiation and TV-AE reporting were 0.17 (.12–.27) and 0.25 (.20–.99) at eThekwini versus 0.18 (.15–.2) and 0.24 (.15–.99) at Verulam/Isipingo (all P > .05). Cox regression analysis revealed that NG/CT treatment initiation (adjusted hazard ratio [aHR], 39.62 [95%CI, 15.13–103.74]) and NG/CT-AE reporting (aHR, 3.38 [95%CI, 2.23–5.13]) occurred faster at eThekwini versus Verulam/Isipingo, while times to TV treatment initiation (aHR, 0.93 [95%CI, .59–1.48]) and TV-AE reporting (aHR, 1.38 [95%CI, .86–2.21]) were similar.ConclusionsPOC testing led to prompt STI management with potential therapeutic and prevention benefits, highlighting its utility as a diagnostic tool in resource-limited settings.

We report a 23% asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) Omicron carriage rate in participants being enrolled into a clinical trial in South Africa, 15-fold higher than in trials before Omicron. We also found lower CD4 + T-cell counts in persons with human immunodeficiency virus (HIV) strongly correlated with increased odds of being SARS-CoV-2 polymerase chain reaction (PCR) positive.

Background Pregnancies occur during HIV-1 vaccine clinical trials, despite requirements for women of reproductive potential to use effective contraception. Deployment of an effective HIV-1 vaccine regimen will likely target adolescents and young adults and therefore safety for pregnant and breastfeeding women will need to be addressed. Methods We performed a retrospective, cross-protocol analysis to identify and compare pregnancy outcomes reported in 53 Phase 1 and Phase 2a HIV-1 vaccine clinical trials conducted by the HIV Vaccine Trials Network (HVTN). Results Two thousand six hundred seventy-three women of reproductive potential were identified and 193 pregnancies were reported. 39 of 53 (74%) studies had at least one pregnancy reported with an overall pregnancy rate of 3.15 per 100 woman-years (w-yr). While active contraception use was required during study participation, 13 of the 53 studies also contained a long-term follow up period during which pregnancy was no longer discouraged. The pregnancy rate during main study participation was 3.09 per 100 w-yr, while pregnancies occurred at a slightly greater rate in the long-term follow up period (3.22 per 100 w-yr). Adverse pregnancy outcomes were reported at similar rates between vaccinees and placebo recipients when vaccine vectors, adjuvant used, or geographic region were examined. Conclusion Although there is considerable heterogeneity amongst the different vaccine trials, there appears to be no obvious indication of increased risk of adverse pregnancy or birth outcomes in these early phase HIV-1 vaccine studies. More complete data on pregnancy outcomes should be collected in early phase HIV-1 vaccine clinical trials to better inform subsequent efficacy trials.

The COVID-19 epidemic of 2019–20 is due to the novel coronavirus SARS-CoV-2. Following first case description in December, 2019 this virus has infected over 10 million individuals and resulted in at least 500,000 deaths world-wide. The virus is undergoing rapid mutation, with two major clades of sequence variants emerging. This study sought to determine whether SARS-CoV-2 sequence variants are associated with differing outcomes among COVID-19 patients in a single medical system. Whole genome SARS-CoV-2 RNA sequence was obtained from isolates collected from patients registered in the University of Washington Medicine health system between March 1 and April 15, 2020. Demographic and baseline clinical characteristics of patients and their outcome data including their hospitalization and death were collected. Statistical and machine learning models were applied to determine if viral genetic variants were associated with specific outcomes of hospitalization or death. Full length SARS-CoV-2 sequence was obtained 190 subjects with clinical outcome data. 35 (18.4%) were hospitalized and 14 (7.4%) died from complications of infection. A total of 289 single nucleotide variants were identified. Clustering methods demonstrated two major viral clades, which could be readily distinguished by 12 polymorphisms in 5 genes. A trend toward higher rates of hospitalization of patients with Clade 2 infections was observed (p = 0.06, Fisher’s exact). Machine learning models utilizing patient demographics and co-morbidities achieved area-under-the-curve (AUC) values of 0.93 for predicting hospitalization. Addition of viral clade or sequence information did not significantly improve models for outcome prediction. In summary, SARS-CoV-2 shows substantial sequence diversity in a community-based sample. Two dominant clades of virus are in circulation. Among patients sufficiently ill to warrant testing for virus, no significant difference in outcomes of hospitalization or death could be discerned between clades in this sample. Major risk factors for hospitalization and death for either major clade of virus include patient age and comorbid conditions.

The early widespread dissemination of Omicron indicates the urgent need to better understand the transmission dynamics of this variant, including asymptomatic spread among immunocompetent and immunosuppressed populations. In early December 2021, the Ubuntu clinical trial, designed to evaluate efficacy of the mRNA-1273 vaccine (Moderna) among persons living with HIV (PLWH), began enrolling participants. Nasal swabs are routinely obtained at the initial vaccination visit, which requires participants to be clinically well to receive their initial jab. Of the initial 230 participants enrolled between December 2 and December 17, 2021, 71 (31%) were PCR positive for SARS-CoV-2: all of whom were subsequently confirmed by S gene dropout to be Omicron; 48% of the tested samples had cycle threshold (CT) values These findings strongly suggest that Omicron has a much higher rate of asymptomatic carriage than other VOC and this high prevalence of asymptomatic infection is likely a major factor in the widespread, rapid dissemination of the variant globally, even among populations with high prior rates of SARS-COV-2 infection.

BackgroundThe COVID-19 epidemic of 2019-20 is due to the novel coronavirus SARS-CoV-2. Following first case description in December, 2019 this virus has infected over 10 million individuals and resulted in at least 500,000 deaths world-wide. The virus is undergoing rapid mutation, with two major clades of sequence variants emerging. This study sought to determine whether SARS-CoV-2 sequence variants are associated with differing outcomes among COVID-19 patients in a single medical system.MethodsWhole genome SARS-CoV-2 RNA sequence was obtained from isolates collected from patients registered in the University of Washington Medicine health system between March 1 and April 15, 2020. Demographic and baseline medical data along with outcomes of hospitalization and death were collected. Statistical and machine learning models were applied to determine if viral genetic variants were associated with specific outcomes of hospitalization or death.FindingsFull length SARS-CoV-2 sequence was obtained 190 subjects with clinical outcome data. 35 (18.4%) were hospitalized and 14 (7.4%) died from complications of infection. A total of 289 single nucleotide variants were identified. Clustering methods demonstrated two major viral clades, which could be readily distinguished by 12 polymorphisms in 5 genes. A trend toward higher rates of hospitalization of patients with Clade 2 was observed (p=0.06). Machine learning models utilizing patient demographics and co-morbidities achieved area-under-the-curve (AUC) values of 0.93 for predicting hospitalization. Addition of viral clade or sequence information did not significantly improve models for outcome prediction.ConclusionSARS-CoV-2 shows substantial sequence diversity in a community-based sample. Two dominant clades of virus are in circulation. Among patients sufficiently ill to warrant testing for virus, no significant difference in outcomes of hospitalization or death could be discerned between clades in this sample. Major risk factors for hospitalization and death for either major clade of virus include patient age and comorbid conditions.FundingSupported by NIH P30EY001730, the Mark J. Daily, MD Research Fund (RVG), the Alida and Christopher Latham Research Fund (RVG, AYL, CSL), NIH K23EY029246 (AYL), US Food and Drug Administration (QYL)

This population epidemiology study characterizes trends in polymerase chain reaction (PCR) test positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Washington State and the Seattle area between March 1 and April 16, 2020, before and after statewide physical distancing guidelines and stay-at-home orders.

Background Digital technologies, especially if used in novel ways, provide a number of potential advantages to clinical research in trials related to human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) and may greatly facilitate operations as well as data collection and analysis. These technologies may even allow answering questions that are not answerable with older technologies. However, they come with a variety of potential concerns for both the participants and the trial sponsors. The exact challenges and means for alleviation depend on the technology and on the population in which it is deployed, and the rapidly changing landscape of digital technologies presents a challenge for creating future-proof guidelines for technology application. Objective The aim of this study was to identify and summarize some common themes that are frequently encountered by researchers in this context and highlight those that should be carefully considered before making a decision to include these technologies in their research. Methods In April 2016, the Global HIV Vaccine Enterprise surveyed the field for research groups with recent experience in novel applications of digital technologies in HIV clinical research and convened these groups for a 1-day meeting. Real-world uses of various technologies were presented and discussed by 46 attendees, most of whom were researchers involved in the design and conduct of clinical trials of biomedical HIV prevention and treatment approaches. After the meeting, a small group of organizers reviewed the presentations and feedback obtained during the meeting and categorized various lessons-learned to identify common themes. A group of 9 experts developed a draft summary of the findings that was circulated via email to all 46 attendees for review. Taking into account the feedback received, the group finalized the considerations that are presented here. Results Meeting presenters and attendees discussed the many successful applications of digital technologies to improve research outcomes, such as those for recruitment and enrollment, participant identification, informed consent, data collection, data quality, and protocol or treatment adherence. These discussions also revealed unintended consequence of technology usage, including risks to study participants and risks to study integrity. Conclusions Key lessons learned from these discussions included the need to thoroughly evaluate systems to be used, the idea that early success may not be sustained throughout the study, that some failures will occur, and considerations for study-provided devices. Additionally, taking these key lessons into account, the group generated recommendations on how to move forward with the use of technology in HIV vaccine and biomedical prevention trials.

Advances in high-throughput sequencing have enabled technologies that probe the adaptive immune system with unprecedented depth. We have developed a multiplex PCR method to sequence tens of millions of T cell receptors (TCRs) from a single sample in a few days. A method is presented to test the precision, accuracy, and sensitivity of this assay. T cell clones, each with one fixed productive TCR rearrangement, are doped into complex blood cell samples. TCRs from a total of eleven samples are sequenced, with the doped T cell clones ranging from 10% of the total sample to 0.001% (one cell in 100,000). The assay is able to detect even the rarest clones. The precision of the assay is demonstrated across five orders of magnitude. The accuracy for each clone is within an overall factor of three across the 100,000 fold dynamic range. Additionally, the assay is shown to be highly repeatable.

Background: Accurate safety monitoring in HIV vaccine trials is vital to eventual licensure and consequent uptake of products. Current practice in preventive vaccine trials, under the HIV Vaccine Trials Network (HVTN), is to capture related side effects in a hardcopy tool. The reconciliation of this tool, 2 weeks after vaccination at the safety visit, is time consuming, laborious, and fraught with error. Unstructured Supplementary Service Data (USSD), commonly used to purchase airtime, has been suggested for collection of safety data in vaccine trials. With saturated access to mobile phones in South Africa, this cheap, accessible tool may improve accuracy and completeness of collected data and prove feasible and acceptable over the hardcopy tool. Objective: The objective of our study is to develop and implement a USSD tool for real-time safety data collection that is feasible and acceptable to participants and staff, allowing for a comparison with the hardcopy tool in terms of completeness and accuracy. Methods: This feasibility study is being conducted at a single study site, the Centre for the AIDS Programme of Research in South Africa eThekwini Clinical Research site, in South Africa. The feasibility study is nested within a parent phase 1/2a preventive HIV vaccine trial (HVTN 108) as an open-label, randomized controlled trial, open to all consenting parent trial participants. Participants are randomly assigned in a 1:1 ratio to the hardcopy or USSD tool, with data collection targeted to the third and fourth injection time points in the parent trial. Online feasibility and acceptability surveys will be completed by staff and participants at the safety visit. We will itemize and compare error rates between the hardcopy tool and the USSD printout and associated source documentation. We hypothesize that the USSD tool will be shown to be feasible and acceptable to staff and participants and to have superior quality and completion rates to the hardcopy tool. Results: The study has received regulatory approval. We have designed and developed the USSD tool to include all the data fields required for reactogenicity reporting. Online feasibility and accessibility surveys in both English and isiZulu have been successfully installed on a tablet. Data collection is complete, but analysis is pending. Conclusions: Several HIV preventive vaccine trials are active in Southern Africa, making tools to improve efficiencies and minimize error necessary. Our results will help to determine whether the USSD tool can be used in future vaccine studies and can eventually be rolled out. Trial Registration: ClincalTrials.gov NCT02915016; https://clinicaltrials.gov/ct2/show/NCT02915016 (Archived by WebCite at http://www.webcitation.org/71h0cztDM) Registered Report Identifier: RR1-10.2196/9396

The two main lineages of T lymphocytes develop from multi potent precursors in the human thymus. The most common type in blood are αβ T cells, which bind to antigenic peptides displayed on the surface of cells by human leukocyte antigen (HLA) molecules. Far less well understood are γδ T cells, which do not bind HLA: peptide complexes and are more prevalent in the gut mucosa. For both lineages, their ability to recognize a diverse array of antigens is mediated by a rearranged Y-like receptor on their surface, the T cell receptor (TCR), composed and of an α and β chain for αβ T cells or a γ and δ chain for γδ T cells. The canonical model for commitment from the precursor to one these two lineages assumes that γ, δ, and β chains rearrange prior to commitment to αβ or γδ T cells. A crucial step towards better understanding the role of γδ T cells is to work out the developmental process. To test the standard model and to understand the γδ TCR repertoire, we use high-throughput sequencing to catalog millions of TCRγ and TCRβ chains from peripheral blood αβ and γδ T cells, from three unrelated individuals. Almost all sampled αβ and γδ T cells have rearranged TCRγ sequences. While sampled αβ T cells have a diverse repertoire of rearranged TCRβ chains, less than 10% of γδ T cells in peripheral blood have a rearranged TCRβ chain. Our data indicate that TCRγ rearranges in all T lymphocytes, consistent with TCRγ rearranging prior to T cell lineage commitment, while rearrangement of the TCRβ locus is restricted, and occurs after T cell precursors commit to the αβ T cell lineage. This result explains the conundrum in T cell leukemia and lymphoma that TCRγ is almost always rearranged and TCRβ is only rearranged in a subset of cancers. As high-throughput sequencing of TCRs is translated into the clinic for monitoring minimal residual for leukemia/lymphoma, our data suggests the sequencing target needs to be TCR γ.

Diversity in T lymphocyte antigen receptors is generated by somatic rearrangement of T cell receptor (TCR) genes and is concentrated within the third complementarity-determining region 3 (CDR3) of each chain of the TCR heterodimer. We sequenced the CDR3 regions from millions of rearranged TCR beta chain genes in naïve and memory CD8(+) T cells of seven adults. The CDR3 sequence repertoire realized in each individual is strongly biased toward specific V(beta)-J(beta) pair utilization, dominated by sequences containing few inserted nucleotides, and drawn from a defined subset comprising less than 0.1% of the estimated 5 x 10(11) possible sequences. Surprisingly, the overlap in the naïve CD8(+) CDR3 sequence repertoires of any two of the individuals is approximately 7000-fold larger than predicted and appears to be independent of the degree of human leukocyte antigen matching.

Background Genotyping technologies enable us to genotype multiple Single Nucleotide Polymorphisms (SNPs) within selected genes/regions, providing data for haplotype association analysis. While haplotype-based association analysis is powerful for detecting untyped causal alleles in linkage-disequilibrium (LD) with neighboring SNPs/haplotypes, the inclusion of extraneous SNPs could reduce its power by increasing the number of haplotypes with each additional SNP. Methods Here, we propose a haplotype-based stepwise procedure (HBSP) to eliminate extraneous SNPs. To evaluate its properties, we applied HBSP to both simulated and real data, generated from a study of genetic associations of the bactericidal/permeability-increasing (BPI) gene with pulmonary function in a cohort of patients following bone marrow transplantation. Results Under the null hypothesis, use of the HBSP gave results that retained the desired false positive error rates when multiple comparisons were considered. Under various alternative hypotheses, HBSP had adequate power to detect modest genetic associations in case-control studies with 500, 1,000 or 2,000 subjects. In the current application, HBSP led to the identification of two specific SNPs with a positive validation. Conclusion These results demonstrate that HBSP retains the essence of haplotype-based association analysis while improving analytic power by excluding extraneous SNPs. Minimizing the number of SNPs also enables simpler interpretation and more cost-effective applications.