2022

Evolutionary consequences of delaying intervention for monkeypox

Philip L F Johnson, Carl T Bergstrom, Roland R Regoes, Ira M Longini, M Elizabeth Halloran, Rustom Antia

The Lancet

September 21, 2022

ABSTRACT

Since May, 2022, clusters of monkeypox infections have caused global concern. At present, this concern has been tempered by the fact that, even when uncontrolled, the number of infections is growing slowly, indicating a reproductive number (R) not much larger than unity. However, the effect of R on the probability of evolution might not be obvious. We suggest that, compared with zoonotic pathogens with large R values, those pathogens with R values just above 1, such as monkeypox virus, have a higher probability of evolution during the timeframe in which the number of cases remains low. Waiting until the number of cases is high would give monkeypox virus—or any emerging pathogen—the opportunity to adapt substantially to humans.

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats

Ira M Longini, Yang Yang, Thomas R Fleming, César Muñoz-Fontela, Rui Wang, Susan S Ellenberg, George Qian, M Elizabeth Halloran, Martha Nason, Victor De Gruttola, Sabue Mulangu, Yunda Huang, Christl A Donnelly, Ana-Maria Henao Restrepo

Clinical Trials

July 22, 2022

ABSTRACT

Background:

The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines.

Methods:

A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units.

Results:

The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm.

Conclusion:

This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Quantifying the importance and location of SARS-CoV-2 transmission events in large metropolitan areas

Alberto Aleta, David Mart´ın-Corral, Michiel A. Bakker, Ana Pastore y Piontti, Marco Ajelli, Maria Litvinova, Matteo Chinazzi,Natalie E. Dean, M. Elizabeth Halloran, Ira M. Longini, Jr., Alex Pentland, Alessandro Vespignani, Yamir Moreno, Esteban Moro

PNAS

June 28, 2022

ABSTRACT

Detailed characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission across different settings can help design less disruptive interventions. We used real-time, privacy-enhanced mobility data in the New York City, NY and Seattle, WA metropolitan areas to build a detailed agent-based model of SARS-CoV-2 infection to estimate the where, when, and magnitude of transmission events during the pandemic’s first wave. We estimate that only 18% of individuals produce most infections (80%), with about 10% of events that can be considered superspreading events (SSEs). Although mass gatherings present an important risk for SSEs, we estimate that the bulk of transmission occurred in smaller events in settings like workplaces, grocery stores, or food venues. The places most important for transmission change during the pandemic and are different across cities, signaling the large underlying behavioral component underneath them. Our modeling complements case studies and epidemiological data and indicates that real-time tracking of transmission events could help evaluate and define targeted mitigation policies.

Ecology and public health burden of Keystone virus in Florida

Christopher J.Henry, Alexander N.Pillai, John A. Lednicky, J. Glenn Morris Jr., Thomas J. Hladish

Epidemics

June 13, 2022

ABSTRACT

Keystone virus (KEYV) is an under-studied orthobunyavirus that is transmitted via both horizontal and vertical cycles involving various mosquito species and vertebrate hosts. Historical evidence indicates that KEYV causes sub-clinical infections in humans, and some case studies draw links between this virus and encephalitis. Given KEYV’s potential to cause human infections, it is plausible that it causes an under-appreciated proportion of both generic viral infections and unidentified viral encephalitis cases. This review summarizes current knowledge of KEYV and its disease dynamics in order to better understand the virus’ medical and economic burden on human populations.

Household secondary attack rates of SARS-CoV-2 by variant and vaccination status: an updated systematic review and meta-analysis

Zachary J. Madewell, Yang Yang, Ira M. Longini Jr, M. Elizabeth Halloran, Natalie E. Dean

medrXiv

January 11, 2022

ABSTRACT

We previously reported a household secondary attack rate (SAR) for SARS-CoV-2 of 18.9% through June 17, 2021. To examine how emerging variants and increased vaccination have affected transmission rates, we searched PubMed from June 18, 2021, through January 7, 2022. Meta-analyses used generalized linear mixed models to obtain SAR estimates and 95%CI, disaggregated by several covariates. SARs were used to estimate vaccine effectiveness based on the transmission probability for susceptibility (VES,p), infectiousness (VEI,p), and total vaccine effectiveness (VET,p). Household SAR for 27 studies with midpoints in 2021 was 35.8% (95%CI, 30.6%-41.3%), compared to 15.7% (95%CI, 13.3%-18.4%) for 62 studies with midpoints through April 2020. Household SARs were 38.0% (95%CI, 36.0%-40.0%), 30.8% (95%CI, 23.5%-39.3%), and 22.5% (95%CI, 18.6%-26.8%) for Alpha, Delta, and Beta, respectively. VEI,p, VES,p, and VET,p were 56.6% (95%CI, 28.7%-73.6%), 70.3% (95%CI, 59.3%-78.4%), and 86.8% (95%CI, 76.7%-92.5%) for full vaccination, and 27.5% (95%CI, -6.4%-50.7%), 43.9% (95%CI, 21.8%-59.7%), and 59.9% (95%CI, 34.4%-75.5%) for partial vaccination, respectively. Household contacts exposed to Alpha or Delta are at increased risk of infection compared to the original wild-type strain. Vaccination reduced susceptibility to infection and transmission to others.

Using social contact data to improve the overall effect estimate of a cluster-randomized influenza vaccination program in Senegal

Gail E Potter, Nicole Bohme Carnegie, Jonathan D Sugimoto, Aldiouma Diallo, John C Victor, Kathleen M Neuzil , M Elizabeth Halloran

Royal Statistical Society C

January 10, 2022

ABSTRACT

This study estimates the overall effect of two influenza vaccination programs consecutively administered in a cluster-randomized trial in western Senegal over the course of two influenza seasons from 2009-2011. We apply cutting-edge methodology combining social contact data with infection data to reduce bias in estimation arising from contamination between clusters. Our time-varying estimates reveal a reduction in seasonal influenza from the intervention and a nonsignificant increase in H1N1 pandemic influenza. We estimate an additive change in overall cumulative incidence (which was 6.13% in the control arm) of -0.68 percentage points during Year 1 of the study (95% CI: -2.53, 1.18). When H1N1 pandemic infections were excluded from analysis, the estimated change was -1.45 percentage points and was significant (95% CI, -2.81, -0.08). Because cross-cluster contamination was low (0-3% of contacts for most villages), an estimator assuming no contamination was only slightly attenuated (-0.65 percentage points). These findings are encouraging for studies carefully designed to minimize spillover. Further work is needed to estimate contamination - and its effect on estimation - in a variety of settings.