Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial.

BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. METHODS: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291. FINDINGS: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053). INTERPRETATION: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. FUNDING: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research.

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials.

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity. Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease. Design, Setting, and Participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023. Main Outcomes and Measures: Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis. Results: Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity. Conclusions and Relevance: In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.

COVID-19 vaccine efficacy in participants with weakened immune systems from four randomized-controlled trials.

BACKGROUND: Although the SARS-CoV-2 vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. METHODS: A post-hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, COVID-19 vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS (NTIS) individuals starting at 14 days after completion of the primary series through the blinded phase for each of the four trials. An analysis of participants living with well-controlled HIV was conducted using the same methods. RESULTS: 3,852/30,351 (12.7%) Moderna participants, 3,088/29,868 (10.3%) Novavax participants, 3,549/32,380 (11.0%) AstraZeneca participants, and 5,047/43,788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (versus placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants vs NTIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with HIV. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared to those with non-tempered immune systems in the four COVID-19 vaccine randomized controlled efficacy trials.

A HIV-1 Gp41 Peptide-Liposome Vaccine Elicits Neutralizing Epitope-Targeted Antibody Responses in Healthy Individuals.

Background: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys. Methods: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12. Results: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations. Conclusions: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine.

Four statistical frameworks for assessing an immune correlate of protection (surrogate endpoint) from a randomized, controlled, vaccine efficacy trial.

A central goal of vaccine research is to characterize and validate immune correlates of protection (CoPs). In addition to helping elucidate immunological mechanisms, a CoP can serve as a valid surrogate endpoint for an infectious disease clinical outcome and thus qualifies as a primary endpoint for vaccine authorization or approval without requiring resource-intensive randomized, controlled phase 3 trials. Yet, it is challenging to persuasively validate a CoP, because a prognostic immune marker can fail as a reliable basis for predicting/inferring the level of vaccine efficacy against a clinical outcome, and because the statistical analysis of phase 3 trials only has limited capacity to disentangle association from cause. Moreover, the multitude of statistical methods garnered for CoP evaluation in phase 3 trials renders the comparison, interpretation, and synthesis of CoP results challenging. Toward promoting broader harmonization and standardization of CoP evaluation, this article summarizes four complementary statistical frameworks for evaluating CoPs in a phase 3 trial, focusing on the frameworks' distinct scientific objectives as measured and communicated by distinct causal vaccine efficacy parameters. Advantages and disadvantages of the frameworks are considered, dependent on phase 3 trial context, and perspectives are offered on how the frameworks can be applied and their results synthesized.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.

Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features.

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.

Study design approaches for future active-controlled HIV prevention trials.

Objectives: Vigorous discussions are ongoing about future efficacy trial designs of candidate human immunodeficiency virus (HIV) prevention interventions. The study design challenges of HIV prevention interventions are considerable given rapid evolution of the prevention landscape and evidence of multiple modalities of highly effective products; future trials will likely be 'active-controlled', i.e., not include a placebo arm. Thus, novel design approaches are needed to accurately assess new interventions against these highly effective active controls. Methods: To discuss active control design challenges and identify solutions, an initial virtual workshop series was hosted and supported by the International AIDS Enterprise (October 2020-March 2021). Subsequent symposia discussions continue to advance these efforts. As the non-inferiority design is an important conceptual reference design for guiding active control trials, we adopt several of its principles in our proposed design approaches. Results: We discuss six potential study design approaches for formally evaluating absolute prevention efficacy given data from an active-controlled HIV prevention trial including using data from: 1) a registrational cohort, 2) recency assays, 3) an external trial placebo arm, 4) a biomarker of HIV incidence/exposure, 5) an anti-retroviral drug concentration as a mediator of prevention efficacy, and 6) immune biomarkers as a mediator of prevention efficacy. Conclusions: Our understanding of these proposed novel approaches to future trial designs remains incomplete and there are many future statistical research needs. Yet, each of these approaches, within the context of an active-controlled trial, have the potential to yield reliable evidence of efficacy for future biomedical interventions.

Baseline malaria infection status and RTS,S/AS01E malaria vaccine efficacy.

Background: The only licensed malaria vaccine, RTS,S/AS01 E , confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy (VE). Methods: 1,500 children aged 5-17 months were randomized to receive four different RTS,S/AS01 E regimens or a rabies control vaccine in a phase 2b clinical trial in Ghana and Kenya. We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods in over 36K participant specimens. We performed a post hoc analysis of VE based on malaria infection status at first vaccination and force of infection. Results: We observed significant and comparable VE (25-43%, 95% CI union 9-53%) against first new infection for all four RTS,S/AS01 E regimens across both follow-up periods (12 and 20 months). Each RTS,S/AS01 E regimen significantly reduced the number of new infections in the 20-month follow-up period (control mean 4.1 vs. RTS,S/AS01 E mean 2.6-3.0). VE against first new infection was significantly higher in participants who were malaria-infected (68%; 95% CI, 50 to 80%) versus uninfected (37%; 95% CI, 23 to 48%) at the first vaccination (P=0.0053) and in participants experiencing greater force of infection between dose 1 and 3 (P=0.059). Conclusions: All tested dosing regimens blocked some infections to a similar degree. Improved VE in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. ( ClinicalTrials.gov number, NCT03276962 ).

High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.

The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300-1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Adults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01.

Broadly neutralizing monoclonal antibodies (mAbs) are being developed for HIV-1 prevention. Hence, these mAbs and licensed oral pre-exposure prophylaxis (PrEP) (tenofovir-emtricitabine) can be concomitantly administered in clinical trials. In 48 US participants (men and transgender persons who have sex with men) who received the HIV-1 mAb VRC01 and remained HIV-free in an antibody-mediated-prevention trial (ClinicalTrials.gov #NCT02716675), we conduct a post-hoc analysis and find that VRC01 clearance is 0.08 L/day faster (p = 0.005), and dose-normalized area-under-the-curve of VRC01 serum concentration over-time is 0.29 day/mL lower (p < 0.001) in PrEP users (n = 24) vs. non-PrEP users (n = 24). Consequently, PrEP users are predicted to have 14% lower VRC01 neutralization-mediated prevention efficacy against circulating HIV-1 strains. VRC01 clearance is positively associated (r = 0.33, p = 0.03) with levels of serum intestinal Fatty Acid Binding protein (I-FABP), a marker of epithelial intestinal permeability, which is elevated upon starting PrEP (p = 0.04) and after months of self-reported use (p = 0.001). These findings have implications for the evaluation of future HIV-1 mAbs and postulate a potential mechanism for mAb clearance in the context of PrEP.

A general framework for inference on algorithm-agnostic variable importance.

In many applications, it is of interest to assess the relative contribution of features (or subsets of features) toward the goal of predicting a response - in other words, to gauge the variable importance of features. Most recent work on variable importance assessment has focused on describing the importance of features within the confines of a given prediction algorithm. However, such assessment does not necessarily characterize the prediction potential of features, and may provide a misleading reflection of the intrinsic value of these features. To address this limitation, we propose a general framework for nonparametric inference on interpretable algorithm-agnostic variable importance. We define variable importance as a population-level contrast between the oracle predictiveness of all available features versus all features except those under consideration. We propose a nonparametric efficient estimation procedure that allows the construction of valid confidence intervals, even when machine learning techniques are used. We also outline a valid strategy for testing the null importance hypothesis. Through simulations, we show that our proposal has good operating characteristics, and we illustrate its use with data from a study of an antibody against HIV-1 infection.

A controlled effects approach to assessing immune correlates of protection.

An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect. To address this limitation, we construct the controlled risk curve of a biomarker, which provides the causal risk of an endpoint if all participants are assigned vaccine and the biomarker is set to different levels. Furthermore, we propose a causal CoP analysis based on controlled effects, where for the important special case that the biomarker is constant in the placebo arm, we study the controlled vaccine efficacy curve that contrasts the controlled risk curve with placebo arm risk. We provide identification conditions and formulae that account for right censoring of the clinical endpoint and two-phase sampling of the biomarker, and consider G-computation estimation and inference under a semiparametric model such as the Cox model. We add modular approaches to sensitivity analysis that quantify robustness of CoP evidence to unmeasured confounding. We provide an application to two phase 3 trials of a dengue vaccine indicating that controlled risk of dengue strongly varies with 50$\%$ neutralizing antibody titer. Our work introduces controlled effects causal mediation analysis to immune CoP evaluation.

Stochastic Interventional Vaccine Efficacy and Principal Surrogate Analyses of Antibody Markers as Correlates of Protection against Symptomatic COVID-19 in the COVE mRNA-1273 Trial.

The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Violence Exposure Among Women in the Sex Industry and Their Children in El Alto, Bolivia: A Comparative Cross-Sectional Study.

We conducted a comparative cross-sectional study to compare the prevalence of exposure to workplace violence and intimate partner violence (IPV) in 125 female sex workers (FSWs) and 125 age-matched control women working in other professions (non-FSWs) and their children in El Alto, Bolivia. Violence exposure was assessed using the Demographic Health Survey Domestic Violence Module. To determine associations between work type and violence exposure, we conducted multivariate logistic regression. One-third of working mothers experienced sexual IPV, regardless of their profession. FSWs experienced higher rates of severe physical IPV and workplace violence. Children of FSWs were approximately three times more likely to be exposed to violence in the workplace. In Bolivia, strategies to reduce exposure to violence within the home and in FSW workplaces are paramount to minimizing negative impacts on women and their children. These findings have implications for policies to improve education, living wages, and social interventions to prevent and mitigate violence against women and children.

Stochastic interventional approach to assessing immune correlates of protection: Application to the COVE messenger RNA-1273 vaccine trial.

BACKGROUND: Stochastic interventional vaccine efficacy (SVE) analysis is a new approach to correlate of protection (CoP) analysis of a phase III trial that estimates how vaccine efficacy (VE) would change under hypothetical shifts of an immune marker. METHODS: We applied nonparametric SVE methodology to the COVE trial of messenger RNA-1273 vs placebo to evaluate post-dose 2 pseudovirus neutralizing antibody (nAb) titer against the D614G strain as a CoP against COVID-19. Secondly, we evaluated the ability of these results to predict VE against variants based on shifts of geometric mean titers to variants vs D614G. Prediction accuracy was evaluated by 13 validation studies, including 12 test-negative designs. RESULTS: SVE analysis of COVE supported post-dose 2 D614G titer as a CoP: estimated VE ranged from 66.9% (95% confidence interval: 36.2, 82.8%) to 99.3% (99.1, 99.4%) at 10-fold decreased or increased titer shifts, respectively. The SVE estimates only weakly predicted variant-specific VE estimates (concordance correlation coefficient 0.062 for post 2-dose VE). CONCLUSION: SVE analysis of COVE supports nAb titer as a CoP for messenger RNA vaccines. Predicting variant-specific VE proved difficult due to many limitations. Greater anti-Omicron titers may be needed for high-level protection against Omicron vs anti-D614G titers needed for high-level protection against pre-Omicron COVID-19.