This blog is the fifth in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the HIV Clinical Research Enterprise page.

The outcomes of HIV clinical trials are often determined by precisely and accurately measuring how specific interventions work biologically in people. Whether tracking immune responses to a preventive vaccine candidate, monitoring changes to the amount of virus in the body, or screening for certain adverse events after administering a novel therapeutic, study teams routinely interact with clinical trial participants to safely obtain, store, transport, and analyze tissue and bodily fluid samples to answer important scientific questions about the impact of an HIV intervention in a laboratory. High quality, reliable laboratory infrastructure is critical to the accuracy and validity of clinical trial results. 

More than 150 NIAID-supported laboratories in 20 countries are addressing the diverse scientific programs of the four clinical trials networks in the Institute’s HIV clinical research enterprise. Since the start of HIV clinical research, laboratory capacities have grown in scope to support an increasing number of global clinical trials, emerging complexities in study protocol design and laboratory testing demands and evolving regulatory requirements for research and licensure.

NIAID is engaging research partners, community representatives, and other public health stakeholders in a multidisciplinary evaluation of its HIV clinical trials networks’ progress toward short- and long-term scientific goals. This process assesses knowledge gained since the networks were last awarded in 2020 to identify an essential path forward based on the latest laboratory and clinical evidence. Future NIAID HIV clinical research investments build on the conclusions of these discussions. 

In the next iteration of HIV clinical trials networks, laboratory functions will continue to evolve to align with scientific priorities and research approaches. Networks will support small early-phase trials, large registrational trials and implementation science research to examine preventive vaccine candidates and non-vaccine prevention interventions, antiviral treatments, HIV curative strategies, and therapies to improve the clinical outcomes of people affected by and living with HIV. Selected studies also will rely on high quality laboratory resources to examine interventions for tuberculosis, hepatitis, mpox and other infectious diseases. Clinical trial networks will need to employ a variety of laboratory types to achieve these objectives.  To increase flexibility and ensure the timeliness and the high quality standards the HIV field relies on for evidence that informs science, licensure and equitable practice, NIAID will have the ultimate authority for laboratory selection and approval.

Efficiency and Versatility 

Laboratory assays for HIV clinical trials continue to expand in quantity and complexity and require proportionate technical expertise and management. Future clinical research needs will include immunologic, microbiologic, and molecular testing, as well as standard chemistries and hematologic assays, with fluctuating volumes across a global collection of research sites. Balancing capacity, efficiency, scalability, and cost will require a mixed methods approach. These may include centralized laboratory testing where feasible and advantageous for protocol-specified tests; standardized processes for rapid assessment and approval of new network laboratories; and validated third-party outsourcing of routine assays to ensure timely turnaround when demands surge. 

Quality and Standardization

Ensuring consistent laboratory operations and high quality laboratory data will require continued compliance with the NIAID Division of AIDS Good Clinical Laboratory Practices and other applicable regulatory guidelines, ongoing external quality assurance monitoring, strong inventory management, importation and exportation expertise, and data and specimen management.

The research community plays an essential role in shaping NIAID’s scientific direction and research enterprise operations. We want to hear from you. Please share your questions and comments at NextNIAIDHIVNetworks@mail.nih.gov.

About NIAID’s HIV Clinical Trials Networks

The clinical trials networks are supported through grants from NIAID, with co-funding from and scientific partnerships with NIH’s National Institute of Mental Health, National Institute on Drug Abuse, National Institute on Aging, and other NIH institutes and centers. There are four networks—Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, the HIV Vaccine Trials Network, the HIV Prevention Trials Network, and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network.

Findings From NIH-Funded Study Could Facilitate Early Treatment of Neonatal Sepsis

Scientists have identified a four-gene signature detectable in newborns’ blood at birth that predicts before symptom onset whether a baby will develop sepsis during the first week of life, according to a study co-funded by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID). Sepsis is a potentially life-threatening condition that arises when the body's response to infection injures its own tissues and organs. Using the newly discovered genetic signature to identify newborns who will develop sepsis could facilitate early treatment and obviate the need to give antibiotics to all newborns with suspected sepsis but lacking a definitive diagnosis. The findings were published today in the journal eBioMedicine. 

Two to 3% of newborns globally develop sepsis, and 17.6% of those babies die. The signs of sepsis in newborns—such as irritability, poor feeding and respiratory distress—are common to many illnesses. Consequently, clinicians sometimes misdiagnose newborn sepsis or suspect it too late, leading to death. If a clinician does suspect that a newborn has sepsis, they give the baby antibiotics pending confirmatory laboratory diagnosis of infection. The most common diagnostic technique takes several days, however, and is often inconclusive. As a result, clinicians often must decide between stopping antibiotics early and risking under-treatment, or giving antibiotics based only on a clinical diagnosis and risking serious side effects and development of antimicrobial resistance.

The NIAID-supported study aimed to find a way to accurately predict sepsis in newborns so it can be diagnosed and treated early while avoiding unnecessary antibiotic use. The researchers conducted their study in a subset of 720 initially healthy, full-term newborns who were enrolled in a larger clinical trial at two community health centers in The Gambia, West Africa. Blood was collected from all babies at birth.

Thirty-three infants were hospitalized within the first month of life for clinical signs suggestive of sepsis. Of those, 21 babies were diagnosed with sepsis, including 15 within the first week of life, which is considered early-onset sepsis. Twelve babies were diagnosed with non-septic localized infections. The researchers matched these 33 babies with 33 healthy controls and analyzed their blood to identify genes that were comparatively more active or less active at birth in each of the four groups. Using machine learning methods, the researchers detected four genes that were comparatively more active at birth only in those newborns who developed early-onset sepsis. The four-gene signature was 92.5% accurate at predicting at birth which of the 66 infants would develop early-onset sepsis. 

The researchers tested the predictive accuracy of this gene signature in a different group of 12 infants whose blood had been collected soon after birth. Half had developed early-onset sepsis, while the other half had remained healthy. The four-gene signature predicted sepsis with 83% accuracy in this group. Further research is needed to determine how well the gene signature predicts early-onset sepsis in much larger groups of newborns.

The study was led by Robert E. W. Hancock, Ph.D.; Tobias R. Kollmann, M.D., Ph.D.; Beate Kampmann, M.D., Ph.D.; and Amy H. Lee, Ph.D. NIAID co-funded the study through its Human Immunology Project Consortium (HIPC) and Immune Development in Early Life program. 

The larger study that enrolled the 720 newborns was called Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity, sponsored by Boston Children's Hospital and funded by NIAID through the HIPC. More information is available in ClinicalTrials.gov at study identifier NCT03246230.

Reference: An et al. Predictive gene expression signature diagnoses neonatal sepsis before clinical presentation. eBioMedicine DOI: 10.1016/j.ebiom.2024.105411 (2024).