Publications

BACKGROUND: Despite advances in respiratory syncytial virus (RSV) immunoprophylaxis, RSV remains a leading cause of severe respiratory illness in infants. Immunity at the site of infection is potentially important yet airway mucosal immunity against RSV infection remains poorly defined.

METHODS: We collected nasal and blood samples across three pediatric cohorts: 1) children presenting to the emergency department with respiratory symptoms; 2) infants and mothers presenting to an urban hospital system across the RSV season; 3) infants born to mothers vaccinated with maternal pre-Fusion (F) vaccine. We analyzed mucosal and serologic anti-RSV antibodies and assessed for factors impacting titer magnitude and durability.

RESULTS: Specimens from 285 infants/young children and 39 mothers were analyzed. Mucosal anti-RSV antibody levels were lower in infants presenting with RSV infection compared to age-matched controls both in infants experiencing their first viral season (p = 0.0011) and older children (p < 0.0001). Higher levels of mucosal antibodies were seen in infants whose mothers received maternal pre-F vaccination, with IgG against RSV fusion protein tightly correlating between infant's serum and nasal compartments (p < 0.0001). However, mucosal anti-RSV IgG waned significantly by 6 months of age (p < 0.0001).

CONCLUSIONS: Higher mucosal anti-RSV antibody levels are associated with protection against RSV-related illness. Current immunoprophylactic strategies drive robust anti-RSV IgG responses in the infant mucosal and serological compartments; however, passive immunity wanes over 6 months. These results suggest that RSV immunization strategies optimizing durable mucosal immunity may protect infants from RSV-related respiratory illness.

The innate immune system is rapidly activated following antigen exposure and plays a critical role in shaping the ensuing adaptive immune responses. In this study, we performed bulk RNA sequencing and proteomic profiling in a cohort of 25 rhesus macaques following Ad26.COV2.S immunization to characterize early innate correlates of vaccine immunogenicity and protection. Our results show that innate immune activation occurred as early as day 1 post-vaccination and demonstrated a systemic enrichment of antiviral interferon pathways, cytokine signaling, and activation of innate immune cell signatures. These early transcriptomic signatures correlated positively with humoral and cellular immune responses at 6 weeks following vaccination and correlated inversely with viral loads following SARS-CoV-2 challenge. Similar correlates of immunogenicity were observed in a cohort of 25 adult healthy participants vaccinated with Ad26.COV2.S. Taken together, these findings highlight the importance of early activation of the innate immune responses following Ad26.COV2.S vaccination in shaping the protective adaptive immune response.IMPORTANCEEarly innate immune responses may shape vaccine immunogenicity and protection. We evaluated responses to Ad26.COV2.S vaccination in rhesus macaques and humans and found that day 1 innate immune signatures correlated with subsequent adaptive responses. These findings suggest that early post-vaccination immune programming influences immunogenicity and protective efficacy months later.

BACKGROUND: The cellular and neutralizing antibody responses to SARS-CoV-2 infection are complex, particularly with multiple and heterogeneous exposures. We sought to understand the changes to the antibody and T-cell repertoire elicited by mildly symptomatic or asymptomatic infections in young adults, and how immune responses to prior vaccination may interact with new viral exposures in this population. Additionally, profiling both aspects of humoral and cellular immunity from a single vial of blood is experimentally challenging.

METHODS: We developed a protocol to recover T-cell receptor (TCR) repertoires from frozen blood clots, i.e., remnant material, retained after coagulation of whole blood for serum recovery and antibody analysis. The method was applied to a subset of participants in a COVID-19 vaccine trial (CoVPN 3006, n = 209 participants). We sequenced TCR repertoires and measured anti-SARS-CoV-2 antibody responses from pre-exposure, post-vaccination, and post-breakthrough blood samples.

RESULTS: Clot material provided suitable genomic DNA for TCR profiling, with vaccination and infection leading to expansions in T-cell responses. Consistent with prior studies, we found that hybrid immunological exposures (vaccination after infection) lead to the greatest antibody potency and spike TCR breadth. When the order of exposure was reversed, we observed evidence of attenuated disease severity (reduced shedding duration and lower peak nasal viral load) in post-vaccination versus primary infections.

DISCUSSION: The protocols described here for recovery of TCR repertoires from remnant coagulated material will facilitate more common estimation of cellular and neutralizing antibody immune responses as potential correlates of protection in large clinical trial cohorts where peripheral blood mononuclear cell (PBMC) acquisition or analysis is otherwise infeasible.

Despite transformative advances in antiretroviral therapy, human immunodeficiency virus (HIV) remains a lifelong condition driven by durable viral reservoirs, chronic immune dysfunction, and complex interactions with host biology, coinfections, and aging. While implementation science is essential to ensure that effective interventions reach populations most affected by HIV, implementation cannot succeed in isolation from continued discovery or from the political and social contexts in which care is delivered. This editorial highlights critical gaps in our understanding of sex-based immunologic differences, tissue-specific viral persistence, resistance evolution, and the long-term inflammatory and metabolic consequences of treated HIV-gaps that directly constrain the durability, equity, and scalability of prevention, treatment, and cure strategies. We further emphasize that successful translation depends on stable policy environments, sustained public investment, and trust-based partnerships with affected communities, without which even highly effective biomedical advances fail to achieve impact. Sustained investment across the full translational spectrum-from basic and mechanistic science through clinical, behavioral, and implementation research-is therefore essential. HIV research has repeatedly served as a model system driving advances across immunology, vaccinology, oncology, aging, and pandemic preparedness, underscoring its broader relevance to human infectious diseases.

The innate immune system is rapidly activated following antigen exposure and plays a critical role in shaping the ensuing adaptive immune responses. In this study, we performed bulk RNA sequencing and proteomic profiling in a cohort of 25 rhesus macaques following Ad26.COV2.S immunization to characterize early innate correlates of vaccine immunogenicity and protection. Our results show that innate immune activation occurred as early as day 1 post-vaccination and demonstrated an systemic enrichment of antiviral interferon pathways, interleukin signaling, and innate immune cell signatures. These early transcriptomic signatures correlated positively with humoral and cellular immune responses at 6 weeks following vaccination and correlated inversely with viral loads following SARS-CoV-2 challenge. Similar correlates of immunogenicity were observed in a cohort of 25 adult healthy participants vaccinated with Ad26.COV2.S. Taken together, these findings highlight the importance of early activation of the innate immune system for Ad26.COV2.S vaccine immunogenicity and protective efficacy.

BACKGROUND: Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.LS and VRC07-523LS mAbs for safety and pharmacokinetics in adults.

METHODS: In this first-in-human phase 1 trial (HVTN 136/HPTN 092), adults without HIV were enrolled at six university-affiliated clinical research sites in the USA. Part A evaluated escalating single intravenous doses or subcutaneous infusion of PGT121.414.LS, in four groups: 3 mg/kg intravenous (treatment group 1; n=3), 10 mg/kg intravenous (treatment group 2; n=4), 30 mg/kg intravenous (treatment group 3; n=3), and 5 mg/kg subcutaneous (treatment group 4; n=3). Part B evaluated repeated sequential intravenous administrations of 20 mg/kg PGT121.414.LS plus 20 mg/kg VRC07-523LS (treatment group 5; n=10) and sequential subcutaneous administrations of 5 mg/kg PGT121.414.LS plus 5 mg/kg VRC07-523LS (treatment group 6; n=10) on days 0, 112, and 224. Participants in treatment groups 1 and 2 were enrolled sequentially, with participants enrolled and randomly assigned to treatment groups 3 and 4 after a review of safety data. Participants in treatment groups 5 and 6 were randomly assigned in blocks after a review of safety data from treatment groups 1-4. The primary endpoints were safety and tolerability of mAbs, serum concentrations and pharmacokinetics of mAbs, and serum neutralising activity, assessed in participants who received all scheduled product administrations. Serum concentrations of each mAb were measured via a multiplex assay, and neutralisation activity against multiple HIV viruses was measured via the TZM-bl assay. Serum concentrations were estimated via an open, two-compartment model with first-order elimination from the central compartment. This study was registered with ClinicalTrials.gov (NCT04212091) and has been completed.

FINDINGS: Between Nov 10, 2020, and Oct 5, 2021, we enrolled 33 participants without HIV: median age was 31 years (range 22-48); 19 were assigned female sex at birth and 11 were assigned male sex at birth. Three participants and four participants were sequentially assigned to treatment groups 1 and 2, respectively, and, after safety review, six participants were randomly assigned to treatment groups 3 (n=3) and 4 (n=3); after safety review, 20 participants were randomly assigned to treatment groups 5 (n=10) and 6 (n=10). Intravenous and subcutaneous infusions were safe and well tolerated, without serious adverse events or dose-limiting toxicities. Dose escalation of PGT121.414.LS from 3 mg/kg to 30 mg/kg (intravenous) resulted in a dose-proportional increase in serum concentration of PGT121.414.LS, whether administered alone or in combination with VRC07-523LS. The estimated elimination half-life of PGT121.414.LS was 71 days (95% CI 66-75), three times that of its parental form, PGT121. The estimated subcutaneous (vs intravenous) bioavailability of PGT121.414.LS was 86·1% (95% CI 64·0-95·5). Neutralisation activities were greater in the higher-dose and dual combination intravenous groups than in the subcutaneous administration groups.

INTERPRETATION: These findings support further evaluation of PGT121.414.LS in combination with other mAbs for HIV-1 prevention.

FUNDING: US National Institute of Allergy and Infectious Diseases and US National Institutes of Health.