Impact of a monitoring and evaluation training in 3 PEPFAR-supported countries.

BACKGROUND: The second phase of the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) transitioned from scaling up HIV prevention and treatment to promoting sustainability and capacity building for programs monitoring performance and evaluating key program indicators. We assessed the success of a monitoring and evaluation (M&E) curriculum designed to build capacity in three PEPFAR-supported countries. METHODS: We customized M&E trainings based on country-specific epidemic control priorities in Ethiopia, Guatemala, and Cameroon. The M&E curriculum included five modules and three evaluation activities to assess impact: (i) in-person pre-post confidence assessment surveys (CAS), (ii) in-person pre-post knowledge tests (PPKT), and (iii) electronic 6-12 months post-training translating knowledge into practice (TKP) surveys. Pre- and post-training results were compared within and across countries and triangulation with the qualitative data evaluated overall success. RESULTS: Among 188 participants attending M&E trainings, 154 (82 %) responded to CAS and 165 (88 %) participants from Ethiopia and Cameroon completed PPKT. Overall CAS scores between pre- and post-test improved [Score mean difference:1.5-1.9]. PPKT indicated statistically significant knowledge gained. One out of five TKP respondents provided direct application examples from the M&E training. CONCLUSION: While feedback was predominantly positive overall, revisions were recommended for three of the five modules. Developing a customizable and adaptable M&E curriculum may sustain countries' ability to monitor their progress towards epidemic control.

IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rßγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.

CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.

CD8+ T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8+ T cell dysfunction showed that interleukin-2 (IL-2)-based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2's effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (Treg) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively. To address this, we developed a cis-targeted CD8-IL2 fusion protein, aiming to selectively stimulate dysfunctional CD8+ T cells in chronic HBV. In a mouse model, CD8-IL2 boosted the number of HBV-reactive CD8+ T cells in the liver without substantially altering Treg or NK cell counts. These expanded CD8+ T cells exhibited increased interferon-γ and granzyme B production, demonstrating enhanced functionality. CD8-IL2 treatment resulted in substantial antiviral effects, evidenced by marked reductions in viremia and antigenemia and HBV core antigen-positive hepatocytes. In contrast, an untargeted CTRL-IL2 led to predominant NK cell expansion, minimal CD8+ T cell expansion, negligible changes in effector molecules, and minimal antiviral activity. Human CD8-IL2 trials in cynomolgus monkeys mirrored these results, achieving a roughly 20-fold increase in peripheral blood CD8+ T cells without affecting NK or Treg cell numbers. These data support the development of CD8-IL2 as a therapy for chronic HBV infection.

Estimated COVID-19 Cases and Hospitalizations Averted by Case Investigation and Contact Tracing in the US.

Importance: Evidence of the impact of COVID-19 case investigation and contact tracing (CICT) programs is lacking, but policy makers need this evidence to assess the value of such programs. Objective: To estimate COVID-19 cases and hospitalizations averted nationwide by US states' CICT programs. Design, Setting, and Participants: This decision analytical model study used combined data from US CICT programs (eg, proportion of cases interviewed, contacts notified or monitored, and days to case and contact notification) with incidence data to model outcomes of CICT over a 60-day period (November 25, 2020, to January 23, 2021). The study estimated a range of outcomes by varying assumed compliance with isolation and quarantine recommendations. Fifty-nine state and territorial health departments that received federal funding supporting COVID-19 pandemic response activities were eligible for inclusion. Data analysis was performed from July to September 2021. Exposure: Public health case investigation and contact tracing. Main Outcomes and Measures: The primary outcomes were numbers of cases and hospitalizations averted and the percentage of cases averted among cases not prevented by vaccination and other nonpharmaceutical interventions. Results: In total, 22 states and 1 territory reported all measures necessary for the analysis. These 23 jurisdictions covered 42.5% of the US population (approximately 140 million persons), spanned all 4 US Census regions, and reported data that reflected all 59 federally funded CICT programs. This study estimated that 1.11 million cases and 27 231 hospitalizations were averted by CICT programs under a scenario where 80% of interviewed cases and monitored contacts and 30% of notified contacts fully complied with isolation and quarantine guidance, eliminating their contributions to future transmission. As many as 1.36 million cases and 33 527 hospitalizations could have been prevented if all interviewed cases and monitored contacts had entered into and fully complied with isolation and quarantine guidelines upon being interviewed or notified. Across both scenarios and all jurisdictions, CICT averted an estimated median of 21.2% (range, 1.3%-65.8%) of the cases not prevented by vaccination and other nonpharmaceutical interventions. Conclusions and Relevance: These findings suggest that CICT programs likely had a substantial role in curtailing the pandemic in most jurisdictions during the 2020 to 2021 winter peak. Differences in outcomes across jurisdictions indicate an opportunity to further improve CICT effectiveness. These estimates demonstrate the potential benefits from sustaining and improving these programs.

An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.

Structural basis of C-terminal ß-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease.

Alzheimer's disease, the most common cause of dementia in the elderly and characterized by the deposition and accumulation of plaques, is composed in part of ß-amyloid (Aß) peptides, loss of neurons, and the accumulation of neurofibrillary tangles. Here, we describe ponezumab, a humanized monoclonal antibody, and show how it binds specifically to the carboxyl (C)-terminus of Aß40. Ponezumab can label Aß that is deposited in brain parenchyma found in sections from Alzheimer's disease casualties and in transgenic mouse models that overexpress Aß. Importantly, ponezumab does not label full-length, non-cleaved amyloid precursor protein on the cell surface. The C-terminal epitope of the soluble Aß present in the circulation appears to be available for ponezumab binding because systemic administration of ponezumab greatly elevates plasma Aß40 levels in a dose-dependent fashion after administration to a mouse model that overexpress human Aß. Administration of ponezumab to transgenic mice also led to a dose-dependent reduction in hippocampal amyloid load. To further explore the nature of ponezumab binding to Aß40, we determined the X-ray crystal structure of ponezumab in complex with Aß40 and found that the Aß40 carboxyl moiety makes extensive contacts with ponezumab. Furthermore, the structure-function analysis supported this critical requirement for carboxy group of AßV40 in the Aß-ponezumab interaction. These findings provide novel structural insights into the in vivo conformation of the C-terminus of Aß40 and the brain Aß-lowering efficacy that we observed following administration of ponezumab in transgenic mouse models.