Human tumor xenograft studies are the primary means to evaluate the biological activity of anticancer agents in late-stage preclinical drug discovery. The variability in the growth rate of human tumors established in mice and the small sample sizes make rigorous statistical analysis critical. The most commonly used summary of antitumor activity for these studies is the T/C ratio. However, alternative methods based on growth rate modeling can be used. Here, we describe a summary metric called the rate-based T/C, derived by fitting each animal's tumor growth to a simple exponential model. The rate-based T/C uses all of the data, in contrast with the traditional T/C, which only uses a single measurement. We compare the rate-based T/C with the traditional T/C and assess their performance through a bootstrap analysis of 219 tumor xenograft studies. We find that the rate-based T/C requires fewer animals to achieve the same power as the traditional T/C. We also compare 14-day studies with 21-day studies and find that 14-day studies are more cost efficient. Finally, we perform a power analysis to determine an appropriate sample size.

SARS-CoV-2 vaccinations were initially shown to substantially reduce risk of severe disease and death. However, pharmacokinetic (PK) waning and rapid viral evolution degrade neutralizing antibody (nAb) binding titers, causing loss of vaccinal protection. Additionally, there is inter-individual heterogeneity in the strength and durability of the vaccinal nAb response. Here, we propose a personalized booster strategy as a potential solution to this problem. Our model-based approach incorporates inter-individual heterogeneity in nAb response to primary SARS-CoV-2 vaccination into a pharmacokinetic/pharmacodynamic (PK/PD) model to project population-level heterogeneity in vaccinal protection. We further examine the impact of evolutionary immune evasion on vaccinal protection over time based on variant fold reduction in nAb potency. Our findings suggest viral evolution will decrease the effectiveness of vaccinal protection against severe disease, especially for individuals with a less durable immune response. More frequent boosting may restore vaccinal protection for individuals with a weaker immune response. Our analysis shows that the ECLIA RBD binding assay strongly predicts neutralization of sequence-matched pseudoviruses. This may be a useful tool for rapidly assessing individual immune protection. Our work suggests vaccinal protection against severe disease is not assured and identifies a potential path forward for reducing risk to immunologically vulnerable individuals.

Background: While the rapid deployment of SARS-CoV-2 vaccines had a significant impact on the ongoing COVID-19 pandemic, rapid viral immune evasion and waning neutralizing antibody titers have degraded vaccine efficacy. Nevertheless, vaccine manufacturers and public health authorities have a number of options at their disposal to maximize the benefits of vaccination. In particular, the effect of booster schedules on vaccine performance bears further study. Methods: To better understand the effect of booster schedules on vaccine performance, we used an agent-based modeling framework and a population pharmacokinetic model to simulate the impact of boosting frequency on the durability of vaccine protection against infection and severe acute disease. Results: Our work suggests that repeated dosing at frequent intervals (three or more times a year) may offset the degradation of vaccine efficacy, preserving the utility of vaccines in managing the ongoing pandemic. Conclusions: Given the practical significance of potential improvements in vaccine utility, clinical research to better understand the effects of repeated vaccination would be highly impactful. These findings are particularly relevant as public health authorities worldwide have reduced the frequency of boosters to once a year or less.

A traditional phase 3 clinical efficacy study for a Zika vaccine may be unfeasible because of the current low transmission of Zika virus (ZIKV). An alternative clinical development approach to evaluate Zika vaccine efficacy (VE) is therefore required, delineated in the US FDA’s Accelerated Approval Program for licensure, which utilizes an anti-Zika neutralizing antibody (Zika NAb) titer correlated with non-human primate (NHP) protection as a surrogate endpoint. In this accelerated approval approach, the estimation of VE would be inferred from the percentage of phase 3 trial participants achieving the established surrogate endpoint. We provide a statistical framework to predict the probability of protection for human participants vaccinated with a purified inactivated ZIKV vaccine (TAK-426), in the absence of VE measurements, using NHP data under a single-correlate model. Based on a logistic regression (LR) with bias-reduction model, a probability of 90% protection in humans is expected with a ZIKV NAb geometric mean titer (GMT) ≥ 3.38 log₁₀ half-maximal effective concentration (EC₅₀). The predicted probability of protection of TAK-426 against ZIKV infection was determined using the two-parameter LR model that fit the calculated VE in rhesus macaques and the flavivirus-naïve phase 1 trial participants’ ZIKV NAb GMTs log₁₀ EC₅₀, measured by a ZIKV reporter virus particle assay, at 1 month post dose 2. The TAK-426 10 µg dose predicted a probability of protection from infection of 98% among flavivirus-naïve phase 1 trial participants.

During online commerce, a customer will typically share his or her mailing address with a merchant to allow product delivery. This creates privacy risks for the customer, where the information may be misused, sold, or leaked by multiple merchants. While physical and virtual PO boxes can reduce the privacy risk, these solutions have associated costs that prevent greater adoption. Here, we introduce the concept of mailing address aliasing, which may offer lower cost and greater control in some cases. With this approach, an alias address is created that maps to the customer's true address. The mapping is kept private from the merchant but shared with the carrier. We discuss the advantages and disadvantages of this approach compared with traditional methods for mailing address privacy. We find that mailing address aliasing is likely to reduce unsolicited mail to a greater extent than physical or virtual PO boxes. However, mailing address aliasing may not be compatible with all merchants' ordering systems.