IDCRC Investigator Profile: Karen Kotloff, MD

University of Maryland School of Medicine Vaccine and Treatment Evaluation Unit
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Karen Kotloff is the John A. Scholl, MD and Mary Louise Scholl, MD Distinguished Professor; head of infectious disease and tropical pediatrics, in the Department of Pediatrics; associate director of clinical research at the Center for Vaccine Development and Global Health; and PI of the University of Maryland, Baltimore VTEU at the University of Maryland School of Medicine.

Kotloff is a pediatric infectious disease physician, conducting clinical trials and studies in infectious diseases for the past 40 years. Her research focuses on measuring infectious disease burden and conducting vaccine trials to reduce that burden, especially from enteric infections. She has conducted trials of vaccines and other interventions to prevent Shigella and other enteric infections such as cholera, typhoid, and Clostridium difficile, respiratory pathogens such as influenza and coronavirus, and invasive bacterial infections such as group A streptococcus and Staph aureus. 

How long have you worked with a VTEU?

I led my first clinical vaccine trial in 1991. We assessed the safety and immunogenicity of an oral attenuated Shigella vaccine and its efficacy in preventing illness following a challenge with a virulent strain. I started working on the VTEU in 1996 under the mentorship of Dr. Myron Levine. My first VTEU project was to lead the University of Maryland, Baltimore (UMB) site as part of the pivotal efficacy trial of the trivalent attenuated intranasal influenza virus vaccine in young children that led to licensure. 

In 2007, I became the principal investigator of the UMB VTEU. I have been especially interested in facilitating clinical testing of vaccines that are impeded in their development for reasons such as safety concerns (group A streptococcus, GAS), lack of commercial appeal related to a burden of disease that is concentrated among low-income countries (e.g., Shigella, cholera), an undefined disease burden (e.g., GAS or specific diarrheal or pneumonia pathogens), or lack of a known protective immunologic response in which case other modalities, such as controlled human infection trials, are needed to evaluate the potential for efficacy (e.g., Shigella, influenza).

Briefly describe the IDCRC-supported trials you’ve worked on.

In 2020, I participated in the ACTT-1 Remdesivir COVID Treatment Trial as the senior investigator at the University of Maryland. I led the Moderna Phase 3 trial at UMB and am the protocol co-chair of the COVID-19 Prevention Network (CoVPN) Phase 3 trial, testing the efficacy of NVX-CoV2373, Novavax’s COVID-19 vaccine, in adults and adolescents. Leveraging this randomized controlled trial, I designed the SNIFF (Swab your Nose Inside to Find Infection) multicenter study to determine whether NVx-CoV2373 prevents SARS-CoV-2 infection, both symptomatic and asymptomatic. This trial will help inform value assessments of vaccinating populations, particularly those who frequently experience asymptomatic or minimally symptomatic infection, to prevent onward transmission. I am also a co-investigator in the Phase 3 pentavalent meningococcal vaccine non-inferiority trial in Mali (DMID 20-20024), the Mix-and-Match trial (DMID 21-0012), and have just received approval for protocol development to evaluate the safety and immunogenicity of adding a mucosal adjuvant (dmLT) to routine oral rotavirus vaccine in Bangladeshi. Learn more about IDCRC Studies

Of these trials, what has been the most impactful or highlight of the work?

Due to a safety concern, the clinical development of group A streptococcal (GAS) vaccines was halted, and a prohibition against human administration of GAS products was included in the Code of Federal Regulations (CFR). I designed, obtained regulatory approvals, worked closely with FDA, and conducted the first VTEU Investigational new drug (IND) clinical trial of a GAS vaccine following a 30-year hiatus, and the CFR prohibition was lifted. Progress including further clinical trials continues to occur to develop a GAS vaccine.  

The two Phase 3 COVID trials at our VTEU site led to emergency use authorization of highly efficacious vaccines in record time. We contributed a large number of demographically diverse participants to this effort and in the process worked within the community to provide education about COVID-19 vaccines. Many lives were saved by these vaccines, and it is our hope that the partnerships we developed with underserved groups in our community positively impacted vaccine acceptance.

What is a strength or example of the importance of the IDCRC during the pandemic and beyond?

The IDCRC brings together some of the brightest and most experienced clinical vaccinologists in the U.S. and provides a platform for them to interface with experts at the NIH Division of Microbiology and Infectious Diseases, the leadership of the IDCRC, and outside experts. This interactive process and its associated organizational structure of expert working groups provide a mechanism for selecting innovative, impactful clinical trials for further development. A clear example of the power of this consortium is the work performed to design, conduct, and publish safety and efficacy data in the face of the rapidly evolving COVID-19 pandemic by both providing scientific input into clinical trial design, offering access to highly experienced, efficient trial sites, and creating platforms for exchange of cutting-edge scientific information.

What other trials are you working on?

I conduct large epidemiologic studies (to measure disease burden and vaccine impact) and clinical trials in low- and middle-income trials in sub-Saharan Africa and South Asia. Some examples include:

  • SANTE: an ongoing randomized, observer-blinded, placebo-controlled trial of programmatic administration of oral azithromycin to 50,000 pregnant women and their infants to reduce infant mortality.
  • VIDA: a case-control trial of the incidence, etiology, and adverse clinical outcomes of medically attended diarrhea in Africa (10,000) following rotavirus vaccine introduction.
  • CHAMPS: a multi-center study of the use of postmortem minimally invasive tissue sampling to elucidate the causes of under-five mortality in low-resource settings.
  • NUTRIMAM: a randomized, controlled feeding study testing the effects of a microbiota-directed complementary food-containing diet on nutritional recovery after acute illnesses in infants and young children.