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Getting infected so that others won't

April 25, 2019 by Mary Hodges

WRAIR insectary research.jpg . Volunteers are bitten by mosquitoes for malaria research at the Walter Reed Army Institute of Research. Photo: WRAIR

Volunteers getting bitten by mosquitoes for malaria research at the Walter Reed Army Institute of Research. Photo courtesy of WRAIR.

The controlled human infection model involves getting infected with a pathogen, but it is a critical step in vaccine development.

Imagine willingly exposing yourself to a potentially deadly disease in the name of science. It sounds scary, but over the course of several decades researchers have used this tactic to test drugs and vaccines. The controlled human infection model (CHIM) is one of the most effective ways to measure efficacy when developing a disease intervention. The CHIM – or a version of it – has been used since the 1900s, when patients were intentionally exposed to dengue and yellow fever. Thankfully, research ethics and clinical trial organization have come a long way since then and these days these tests are performed in a safe and well regulated environment.

The benefit of CHIM

Developing a vaccine is a process that can take decades and require hundreds of millions of dollars. Spending this much time and money on a product can be an extremely risky investment. Researchers can use the CHIM as a faster and easier way to figure out if a vaccine candidate is worth investing in. The human infection model is used in an early clinical trial, typically in the United States or another high-income country, and can usually give a good read on the vaccine’s effectiveness. This is a critical step before a costly, larger Phase 3 study is begun.

But how do researchers convince volunteers to agree to be infected with a pathogen? Simply put, these studies are extremely safe, well regulated, and volunteers are constantly tested and treated with medicine at the first sign of an infection. In the three decades that the Walter Reed Army Institute of Research (WRAIR) has been exposing volunteers to malaria, not one person has been hospitalized. The CHIM has played a role in many of the vaccines available today, including cholera, typhoid, and many others.

Some of PATH’s work in vaccine development harnesses CHIM studies to know which vaccine candidates show the most promise. We also coordinate the CHIM Consortium, a network of clinical research sites and investigators skilled in these models. The group’s shared learnings and collective problem solving accelerates vaccine developing using CHIM approaches.

Malaria and the human infection model

Malaria remains one of the world’s toughest global health challenges and a vaccine could have a profound effect on the malaria burden. The decades-long journey of the development of a malaria vaccine has been difficult, but the introduction of the world’s first controlled human malaria infection (CHMI) has been integral to the work of PATH and its partners.

The introduction of the CHMI was a turning point in malaria research and helped accelerate the development of many lifesaving drug candidates and RTS,S, the world’s first malaria vaccine to be implemented in parts of three African countries. In a typical malaria vaccine trial, volunteers are either bitten by mosquitoes who are infected with malaria or have malaria sporozoites injected into their bodies. In the trials where volunteers interact with infected mosquitoes, volunteers sit in a room where a cup is placed against their skin. Inside the cup are several mosquitoes that proceed to feed on the human – sometimes for several hours! Volunteers are closely monitored over the next couple of weeks and if they are infected with malaria, they will receive antimalarial drugs immediately – preventing them from ever getting sick from the disease.

PATH has conducted several CHMI studies at WRAIR over the years, many of which supported the development of RTS,S. The WRAIR insectary produces more than 10,000 mosquitoes per week in support of clinical and preclinical malaria research.

Researchers at the Walter Reed Army Institute of Research breed 10,000 mosquitoes per week for malaria research. Photo: PATH

The Walter Reed Army Institute of Research breeds 10,000 mosquitoes per week for malaria research. Photo: PATH.

The CHIM and diarrheal diseases

PATH and our partners have used the CHIM a little differently when it comes to vaccine research for Enterotoxigenic Escherichia coli (ETEC). Approximately 500,000 children die every year from diarrheal diseases and ETEC and Shigella are believed to account for more than 15 percent of these deaths.

Scientists have used the model to determine the lowest challenge dose of the pathogen that can be used in vaccine tests in order to successfully measure effectiveness. A lower challenge dose can more accurately assess a real world case and prevent a vaccine candidate that might have a lot of potential in endemic settings from being discarded too prematurely.

Scientists have also used the challenge model in its more traditional sense to look at more specific strains of both ETEC and Shigella, which helped to develop improved versions of available vaccines.

The future of the challenge model

As the research and development community develops new, more effective, and lower cost vaccines for low- and middle-income countries, the challenge model will continue to be an essential tool for scientists, investors, and the patients they eventually reach. Critical investments into improving challenge models and investing in challenge models for new diseases are needed to maintain the need for these crucial treatments/interventions.

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