Thoughts leaders believe infectious disease treatment is in the middle of a sea change, moving from antibiotics to antibodies.
The closing plenary session of ID Week 2017 looked ahead to the fight against infectious diseases. James Crowe, Jr, MD, Vanderbilt University Medical Center, Nashville, Tennessee, struck an optimistic note. “I believe we are in the midst of a sea change in moving from antibiotics to antibodies to combat infectious diseases,” he said.
Traditional vaccine development is a laborious failure-and-success process that can take decades. The old timetable just won’t work any longer. “Antibody technology is mature enough and affordable enough to now be considered as a first approach,” said Dr. Crowe. The path from the discovery of an antigenic target to antibody availability is measured in months, not decades. Formulations with half-lives of up to 90 days are being developed. The manufacture of antibodies and their safe administration is well established. All these facts argue for antibody-based strategies as the go-to tool in infectious diseases.
Structure-based vaccines (reverse vaccinology) have been a research goal for decades. The approach identifies an antibody to the microbe of concern and then works backward to identify the epitope. The strategy has been successful in proof-of-concept studies for the Marburg, Ebola, influenza, Zika, chikungunya, and dengue viruses.
To this end, Dr. Crowe is spearheading the Human Immunome Program that audaciously seeks to determine the sequence of every antibody and T-cell receptor. The immunome is the complete set of recombined immune receptor genes. The human genome with its 20,000-30,000 genes pales in comparison to the genetic complement of the immunome, which may be 1012 or more greater numerically. It’s an immense project, but the potential payoffs are equally immense. The work would clarify how antigenic reservoirs are stable (or not) over time; antigenic targets that are fruitful for vaccine development and those (like autoimmune-associated epitopes) that should be avoided; and how diseases change the terrain of the immunome.
New tools not only have the potential of disease therapy; they can be harnessed for the eradication of microbial pathogens. This aspect of 21st-century infectious disease was discussed by Christopher Karp, MD, Director of Global Health Discovery and Translational Sciences at the Bill and Melinda Gates Foundation (BMGF), Seattle, WA.
The BMGF global health-related programs include the eradication of polio and malaria. The job with polio is not done, even with the historic success of the Salk and Sabin vaccines. Global hotspots remain, which can be the seed for a resurgence of the disease. Efforts have resulted in the improved genetic stability of the Sabin virus strain, with the first-in-human clinical trial that began in May 2017.
Malaria is not a problem in the developed world, especially in wealthy countries. But, in poor and under-developed nations, malaria remains a scourge, with 212 million cases and 429,000 deaths in 2016, according to the World Health Organization (WHO). Ninety percent of cases are in sub-Saharan Africa and 70% involve children under 5 years of age. Dr. Karp and his BMGF colleagues are seeking to “bend the curve” from a potential increase to eradication.
Goals include the elimination of the plasmodium parasite from humans, the establishment of complete cure in the hotspots, and ceasing the transmission from mosquito-to-human and vice-versa. The latter focuses on “choke points” such as blocking the path of the parasite to the liver, which occurs within hours of mosquito-human contact. Development of a “rational vaccinology” approach using identified Plasmodia surface epitopes is already underway. Other strategies include genetically subverting the inheritance of genes that drive the infection and rendering female mosquitoes sterile using the Wolbachia bacterium. The bacterial approach has been successful in proof-of-concept studies in blocking the transmission of dengue and Zika viruses by mosquitoes.
David Thomas, MD, Johns Hopkins Medicine, Baltimore, MD, discussed the eradication of hepatitis C virus (HCV). HCV is a frustrating disease. It can be eradicated but only by changing the application of medical care and overcoming the societal levels of indifference to a disease that typically afflicts those who are less fortunate and challenged by abuse issues.
“You can go out and find every HCV-infected individual,” asserted Dr. Thomas. Detection of HCV antibody, RNA, or core antigen can be done now using rapid point-of-care tests. The infection can be halted by stopping viral replication. “This is an incredibly weak virus. It replicates only in the cytoplasm of hepatocytes and has no nuclear reservoir so it has to replicate continuously. If you stop replication you eradicate infection,” said Dr. Thomas. Indeed, a 12-week oral regimen of sofosbuvir and velpatasvir works.
If HCV could be eradicated in humans, the infection would forever be done, since we are the only host for it. And here is where the problem lies. HCV is an under-treated disease. In resource-poor settings, the main source of infection has always been and still is, unsafe medically-supervised injections. In resource-rich countries, illicit injection drug use is the main driver, with young (20 to 29 years of age), white, non-urban males being driving the recent 3-fold increase in the prevalence of HCV since 2010 in the United States.
Addressing HCV will require a shift from the current system—where someone is treated when they come to a medical clinic—to a public health approach where disease prevention in the community setting is the norm. This approach has worked elsewhere, most notably Iceland.
The current medically-oriented approach will not keep pace with the increasing number of cases of HCV. In the current reality, eradicating HCV would take hundreds of years. Rather, argues Dr. Thomas, “we need a precision public health approach to eliminate existing HCV infection that includes expanded testing, new models of public care, strengthened public health infrastructure, treatment that is longer acting and lower cost, and prevention strategies.”
“We can eradicate HCV with treatment, [but,] we keep waiting for someone to walk into a clinic. That doesn’t work. We need a public health approach to a public health problem. Finally, we have to overcome the silence surrounding HCV as a world and as a nation,” he opined.
James E. Crowe Jr.: PaxVax: Scientific Advisor , Consulting fee; Takeda: Scientific Advisor , Consulting fee and Research grant; Sanofi: Consultant , Consulting fee , Licensing agreement or royalty and Research grant; Sanofi Pasteur: Investigator , Licensing agreement or royalty; Novavax: Consultant , Consulting fee; Regeneron: Consultant , Consulting fee; Mapp Biopharmaceutical: Investigator , Licensing agreement or royalty; Moderna: Investigator , Grant recipient; Inovio: Collaborator , Research grant; Atreca: Collaborator , Grant recipient
Christopher Karp: none
David Thomas: UpToDate: Editor, Salary; Oxford University Press: Editor, Salary; Merck: Scientific Advisor, Consulting fee
Closing Plenary: 21st Century Cures in Infectious Disease
Monoclonal Antibodies for Infectious Diseases: Why We are on the Threshold of a Major Therapeutic Revolution
James E. Crowe Jr., MD, Vanderbilt University Medical Center, Nashville, TN
Pathogen Eradication: The View Ahead
Christopher Karp, MD, Global Health Discovery & Translational Sciences, Bill & Melinda Gates Foundation, Seattle, WA
The Pivotal Role of Treatment in the Elimination of HCV
David Thomas, MD, MPH, Johns Hopkins University School of Medicine, Baltimore, MD
Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at firstname.lastname@example.org.