Efficacy of Messenger RNA-1273 Against Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition in Young Adults From March to December 2021.

Background: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults. Methods: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants. Results: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group. Conclusions: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk. Clinical Trials Registration: NCT04811664.

Cross-protocol assessment of induction and durability of VISP/R in HIV preventive vaccine trial participants.

Candidate HIV vaccines are designed to induce antibodies to various components of the HIV virus. An unintended result of these antibodies is that they may also be detected by commercial HIV diagnostic kits designed to detect an immune response to HIV acquisition. This phenomenon is known as Vaccine-Induced Seropositivity/Reactivity (VISP/R). In order to identify the vaccine characteristics associated with VISP/R, we collated the VISP/R results from 8,155 participants from 75 phase 1/2 studies and estimated the odds of VISP/R by multivariable logistic regression and 10-year estimated probability of persistence in relation to vaccine platform, HIV gag and envelope (env) gene inserts, and protein boost. Recipients of viral vectors, protein boosts, and combinations of DNA and viral-vectored vaccines had higher odds of VISP/R compared to those who received DNA-only vaccines (odds ratio, OR = 10.7, 9.1, 6.8, respectively, p<0.001). Recipients of gp140+ env gene insert (OR = 7.079, p<0.001) or gp120 env (OR = 1.508, p<0.001) had higher odds of VISP/R compared to those participants who received no env. Recipients of gp140 protein had higher odds of VISP/R than those that did not receive protein (OR = 25.155, p<0.001), and recipients of gp120 protein, had lower odds of VISP/R than those that did not receive protein (OR = 0.192, p<0.001). VISP/R persisted at 10 years in more recipients of env gene insert or protein compared to those who did not (64% vs 2%). The inclusion of gag gene in a vaccine regimen had modest effects on these odds and was confounded by other covariates. Participants receiving gp140+ gene insert or protein were most often reactive across all serologic HIV tests. Conclusions from this association analysis will provide insight into the possible impact of vaccine design on the HIV diagnostic landscape and vaccinated populations.

Rapid Development of an Integrated Network Infrastructure to Conduct Phase 3 COVID-19 Vaccine Trials.

Importance: The COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts. Observations: To support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing clinical and laboratory infrastructure, community partnerships, and research expertise to quickly pivot clinical trial sites to conduct COVID-19 vaccine trials as soon as the investigational products were ready for phase 3 testing. The mission of CoVPN was to operationalize phase 3 vaccine trials using harmonized protocols, laboratory assays, and a single data and safety monitoring board to oversee the various studies. These trials, while staggered in time of initiation, overlapped in time and course of conduct and ultimately led to the successful completion of multiple studies and US Food and Drug Administration-licensed or -authorized vaccines, the first of which was available to the public less than 1 year from the discovery of the virus. Conclusions and Relevance: This Special Communication describes the design, geographic distribution, and underlying principles of conduct of these efficacy trials and summarizes data from 136 382 prospectively followed-up participants, including more than 2500 with documented COVID-19. These successful efforts can be replicated for other important research initiatives and point to the importance of investments in clinical trial infrastructure integral to pandemic preparedness.

Impact of Point-of-Care Testing on the Management of Sexually Transmitted Infections in South Africa: Evidence from the HVTN702 Human Immunodeficiency Virus Vaccine Trial.

BACKGROUND: Alternative 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: POC testing led to prompt STI management with potential therapeutic and prevention benefits, highlighting its utility as a diagnostic tool in resource-limited settings.

High Asymptomatic Carriage With the Omicron Variant in South Africa.

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.

High Rate of Asymptomatic Carriage Associated with Variant Strain Omicron.

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 <25 and 18% less than 20, indicative of high titers of asymptomatic shedding. Asymptomatic carriage rates were similar in SARS-CoV-2 seropositive and seronegative persons (27% respectively). These data are in stark contrast to COVID-19 vaccine studies conducted pre-Omicron, where the SARS-CoV-2 PCR positivity rate at the first vaccination visit ranged from <1%-2.4%, including a cohort of over 1,200 PLWH largely enrolled in South Africa during the Beta outbreak. We also evaluated asymptomatic carriage in a sub study of the Sisonke vaccine trial conducted in South African health care workers, which indicated 2.6% asymptomatic carriage during the Beta and Delta outbreaks and subsequently rose to 16% in both PLWH and PHLWH during the Omicron period.

A retrospective analysis of incident pregnancy in phase 1 and 2a HIV-1 vaccine study participants does not support concern for adverse pregnancy or birth outcomes.

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.

Hospitalization and mortality associated with SARS-CoV-2 viral clades in COVID-19.

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.

Outcomes associated with SARS-CoV-2 viral clades in COVID-19.

Background 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. Methods 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 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. Findings 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 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. Conclusion 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.

Using Mobile Technology (pMOTAR) to Assess Reactogenicity: Protocol for a Pilot Randomized Controlled Trial.

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.

Using Digital Technologies in Clinical HIV Research: Real-World Applications and Considerations for Future Work.

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.

Ultra-sensitive detection of rare T cell clones.

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.

Deep sequencing of the human TCRγ and TCRß repertoires suggests that TCRß rearranges after αß and γδ T cell commitment.

T lymphocytes respond to a broad array of pathogens with the combinatorial diversity of the T cell receptor (TCR). This adaptive response is possible because of the unique structure of the TCR, which is composed of two chains, either αß or γδ, that undergo genetic rearrangement in the thymus. αß and γδ T cells are functionally distinct within the host but are derived from a common multipotent precursor. The canonical model for T cell lineage commitment assumes that the γ, δ, and ß chains rearrange before αß or γδ T cell commitment. To test the standard model in humans, we used high-throughput sequencing to catalog millions of TCRγ and TCRß chains from peripheral blood αß and γδ T cells from three unrelated individuals. Almost all sampled αß and γδ T cells had rearranged TCRγ sequences. Although sampled αß T cells had a diverse repertoire of rearranged TCRß chains, less than 4% of γδ T cells in peripheral blood had a rearranged TCRß chain. Our data suggest that TCRγ rearranges in all T lymphocytes, consistent with TCRγ rearranging before T cell lineage commitment. However, rearrangement of the TCRß locus appears to be restricted after T cell precursors commit to the αß T cell lineage. Indeed, in T cell leukemias and lymphomas, TCRγ is almost always rearranged and TCRß is only rearranged in a subset of cancers. Because high-throughput sequencing of TCRs is translated into the clinic for monitoring minimal residual for leukemia/lymphoma, our data suggest the sequencing target should be TCRγ.

Overlap and effective size of the human CD8+ T cell receptor repertoire.

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.

A systematic search for SNPs/haplotypes associated with disease phenotypes using a haplotype-based stepwise procedure.

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.