Vital Connections, Global Impact

Science Changing Life

Vital Connections, Global Impact

Science Changing Global Health 2

GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH

Every year, hundreds of millions of people around the world are impacted by infectious diseases. Old foes, such as flu, malaria and tuberculosis, continue to evade elimination and eradication efforts, while largescale outbreaks of emerging infectious diseases pose significant threats to populations across the globe.

To ensure the future of human health worldwide, new technologies, vaccines, diagnostics and drugs are needed to rapidly detect, prevent and cure infections before they become global health emergencies.

A transformative vision for global health research is needed to achieve this goal, and Scripps Research is uniquely positioned to deliver that, given its long history of excellence in infectious disease research. Some of the many diseases researched, including flu, HIV, TB, arboviruses and viral hemorrhagic fevers, impact the most vulnerable populations around the globe and present serious health threats to the United States.

Drawing on wide-ranging expertise in drug discovery, vaccine design and disease detection, the Global Health Initiative at Scripps Research fosters multidisciplinary research aimed at reducing the burden of disease worldwide. By establishing a unique global health research and training program, Scripps Research will leverage its scientific leadership to transform our ability to detect, prevent, and cure infectious disease.

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Detect. Prevent. Cure.

As a result of expanding and increasingly mobile human populations, infectious diseases in particular have demonstrated their ability to cause unpredictable, widespread health and economic disruption. In today’s interconnected world, these new challenges require urgent action.

The Global Health Initiative at Scripps Research will merge our cross-disciplinary strengths in basic and translational research to accelerate the discovery and development of medicines, vaccines and therapeutic strategies.

The Initiative focuses on three key pillars that leverage the long-standing expertise in global health research at Scripps Research to ensure a world that is safer and better prepared for the threats from infectious diseases via: • The development of technologies and computational tools for ultra-rapid detection and forecasting of infectious disease.

• The creation of novel vaccines to prevent and eradicate some of the most pressing human pathogens.

• The discovery and early-stage development of medicines and effective drugs against wide-ranging pathogens and human diseases.

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GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH

More information globalhealth.scripps.edu

Contact us

globalhealth@scripps.edu

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Science Changing Immunity

OUTSMARTING

OUTBREAKS Scripps Research scientists develop super-powered vaccines and therapeutics against HIV, flu and other deadly viruses

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Ever wondered why flu vaccines don’t always protect you from the flu? Or why more than three decades after the cause of AIDS was first identified, there is still no approved vaccine for HIV? The simple answer: some viruses are especially tricky. Their genomes evolve incessantly, making them slippery targets.

Like criminals donning disguises to escape the police, certain viruses can rapidly change their appearance, evading detection and eradication. Now, however, science is closing in on them.

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Science Changing Immunity

The hub of a global network of

Allergy and Infectious Disease of the

collaborators, scientists at Scripps

National Institutes of Health. “If these

Research are designing and testing

strategies prove effective in humans,

a new class of vaccines and drugs

they will represent a leap forward in

to defeat these evasive pathogens.

our ability to manage and prevent the

Their strategy is based on a class of

spread of infectious disease.”

immune system proteins called broadly neutralizing antibodies (bnAbs) that possess a kind of superpower: the

Devious viruses meet powerful antibodies

ability to inactivate a remarkably wide

“In the past, much of the interaction between vaccines, the immune system and pathogens was invisible to us.

Now we can observe these interactions in detail—at the subatomic level, in some cases.”

Andrew Ward, PhD, Scripps Research

range of virus strains. The ability stems

Vaccines typically work by exposing

from the property of bnAbs to recognize

the immune system to weakened

the more stable regions of the outer

or inactivated viruses, or to just a

envelope, the exposed portion of

portion of a virus. When the vaccine

viruses that is typically targeted

is administered to a person, it lacks

by antibodies.

the ability to cause illness but retains enough of the virus’s original shape

This past year has marked several

and content— collectively referred to as

milestones in the pursuit of these

“antigens”—that the body recognizes

“universal” therapies. Last fall, for

it as foreign. To fight the virus, white

instance, Scripps Research scientists

blood cells produce antibodies capable

reported engineering a prototype of

of binding to it at certain locations,

a broadly-neutralizing flu therapy that

known as epitopes. If a person is later

protected mice from multiple strains of

exposed to the live virus, the immune

influenza known to affect humans. And

system then “remembers” the vaccine

in t he past six months, the International

encounter and quickly ramps up its

AIDS Vaccine Initiative (IAVI) launched

defenses to vanquish the invader.

two clinical trials to test vaccines developed by Scripps Research

Unfortunately, not all viruses are readily

scientists and their collaborators.

managed. Flu, HIV and other rapidly mutating viruses present a daunting

“We’ve reached a watershed moment in

challenge, as their genomes continually

the field of immunology, where decades

evolve. Thus, the epitopes that

of research are now coming to fruition in

antibodies target to keep us free from

experimental vaccines and drugs,” says

infection are also ever changing.

Dennis Burton, PhD, co-chair of the

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Department of Immunology and

“Scientists were able to develop

Microbiology at Scripps Research and

effective vaccines against polio,

head of the Center for HIV/AIDS Vaccine

smallpox and measles in large part

Immunology and Immunogen Discovery,

because the neutralizing epitopes on

a national research consortium

those viruses are relatively stable,”

supported by the National Institute for

says Ian Wilson, DPhil, chair of the

GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH

Department of Integrative Structural and Computational Biology at Scripps

Antibody Anatomy 101

Research. “But HIV and influenza mutate rapidly, so classic approaches result in

Antigen

vaccines that are quickly outpaced by

Region of virus or other pathogen recognized by antibody.

viral evolution.”

Antigen binding site

In the case of flu, the virus has months to evolve between the time annual

Variable region

vaccine production begins and flu season hits. Adding to the challenge, new strains and subtypes of flu not targeted by the vaccine can enter the human population from animals, mainly pigs and birds. In comparison to flu, many more different strains of HIV circulate among infected people at any

Light chain

given time, and even a single person can carry hundreds of thousands of variants of the virus. A drug or vaccine

Heavy chain

Constant region

targeting one strain might work for a time only to have a mutated form emerge that isn’t recognized by the therapies.

The excitement over bnAbs stems from their potential to bring this molecular arms race to an end. The first bnAbs to HIV were discovered in the early nineties

by Burton and Carlos Barbas at Scripps Research and by scientists in Vienna, Austria. In 2002, Burton led an effort by the newly formed Neutralizing Antibody Center of IAVI at Scripps Research to

When the immune system encounters a virus or other pathogen, it produces antibodies that neutralize the pathogen by targeting molecular structures referred to as antigens.

find and elicit more bnAbs, preferably with greater potency.

In 2006, after analyzing 1,800 blood samples from HIV-infected people in parts of Africa, India, Southeast Asia, Australia, the United Kingdom and the United States in an effort dubbed IAVI

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Science Changing Immunity Images of antibodies bound to surface glycoproteins of HIV (blue/purple), influenza (red/orange), and Ebola (yellow/green) viruses, generated by electron microscopy and X-ray crystallography. Scripps Research scientists are using state-of-theart structural biology to study interactions between viruses and antibodies to develop more effective vaccines and therapies.

Image courtesy of Charles Murin, Ward lab.

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Protocol G, the team found two potent

hinges on a forensic genomic analysis,

“In the past, much of the interaction

bnAbs in the white blood cells of one

tracing evolutionary steps that take

between vaccines, the immune

woman. In 2009, Burton and his team

place in a person’s body between an

system and pathogens was invisible

reported in Science that the woman’s

early progenitor antibody and a fully

to us,” says Ward, a professor in the

antibodies in laboratory tests proved

fledged bnAb. With a roadmap of that

Department of Integrative Structural

capable of neutralizing 70 percent of

progression in hand, they then set

and Computational Biology.

162 different HIV strains.

out to devise ways to reproduce the

“Now we can observe these

process through vaccination.

interactions in detail—at the atomic level, in some cases. It takes much

In the time since Burton and his colleagues discovered bnAbs against

The state-of-the-art cryo-electron

of the guesswork out of determining

HIV, many others have been identified.

microscopy (cryo-EM) suite at Scripps

what’s working and what is not.”

Researchers also have deciphered

Research has proven vital to studying

quite a bit about what makes this

the molecular intricacies of how the

type of antibody so effective against

immune system and viruses interact.

viruses. Over years of battling HIV in an

Using cryo-EM—which involves deep

Last fall, IAVI announced the start of

infected person’s body, the antibodies

freezing antibodies and surface

a phase 1 clinical trial to test a

collect genetic mutations that morph

antigens from pathogens in liquid

vaccine developed in the laboratory

the molecular makeup at the tips of

ethane and then scanning the samples

of William Schief, PhD, a professor in

their Y-shaped arms. These adaptions

with an electron beam—the team has

the Department of Immunology and

target regions of HIV’s envelope

captured atomic

Microbiology at Scripps Research.

that retain a consistent shape even

resolution images of bnAbs binding

The vaccine is the first in a sequence

as other parts of the virus morph,

to HIV and influenza viruses. These

of engineered vaccine candidates

so the antibodies can recognize a

efforts, led by Scripps Research

designed to stimulate the immune

broad range of HIV strains. BnAbs are

Professor Andrew Ward, PhD, have

system to initiate a key first step

exquisitely adapted to home in on and

opened new avenues for structural

in the generation of bnAbs against HIV.

aggressively bind to HIV. Burton and

biology research on these

Wilson discovered, for example, that

difficult targets.

the antibodies have extra-long loops

There’s a lot that seems to be working.

“This is just the first step in what would be a multistage vaccination strategy.

that act like super Velcro to better cling

Ward, and his colleague, Scripps

No one has ever created or even

to HIV virus, which are notoriously

Research Professor Lars Hangartner,

conceived of a vaccine quite like this,”

devoid of desirable molecular

PhD, recently developed a technique

says Schief, who is director of vaccine

surface features.

for using cryo-EM to rapidly analyze

design for IAVI’s Neutralizing Antibody

the outcome of experimental vaccines

Center. “If we can make this work for

against HIV and other pathogens.

HIV, it could be a model for universal

Their new methodology lets scientists

vaccines against other pathogens.”

From discovery to design Merging research on the immune

quickly assess the full spectrum of

system, viral pathogens, structural

antibodies a person produces in

The other IAVI-led phase 1 HIV-vaccine

biology and vaccine design, the

response to an infection or vaccine

clinical trial, which was announced

Scripps Research team has recently

and determine if these antibodies are

this March, will test a different vaccine

made significant progress in

likely to be effective against

candidate that Ward and Wilson helped

engineering a series of vaccines that

the pathogen.

design with John Moore and Rogier

could be administered in stages to

Sanders at Weill Cornell Medical

coax the immune system to make

College. The vaccine is the first to use

bnAbs against HIV. Their strategy

a version of the highly fragile outer

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Science Changing Immunity

shell of HIV–a protein called Env that is

of collaborators, primarily at Janssen,

shaped like a three-pronged spike—that

engineered a prototype antibody drug

maintains its natural shape. It has shown

capable of protecting against numerous

promising results in preclinical tests.

strains of influenza virus.

Flu Snapshot

“Llamaceuticals” to the rescue

The advance, reported in the journal

During the 2016/2017

The Scripps Research team is also

attention from media outlets, including

flu season*, vaccines

applying their expertise in bnAb

The New York Times, Smithsonian

vaccines to develop new therapies for

Magazine, Axios, BBC and PBS. I t even

flu and malaria, studies supported by the

garnered an enthusiastic blog post from

Bill & Melinda Gates Foundation.

Francis Collins, MD, PhD, director of the

prevented:

Science last November, received wide

National Institutes of Health.

As much as 20 percent of the U.S. influenza illnesses

population gets the flu each year, and

To create the drug, the scientists

of those people, around 200,000 are

pursued a different approach than

hospitalized. The flu season of 2017-

for HIV. Instead of prompting the

2018 was the worst since 2010, with

immune system to produce a single

nearly a million people hospitalized and

broadly neutralizing antibody, they

an estimated 79,000 deaths.

immunized llamas and then engineered a multidomain antibody by tethering

medical visits

Annual vaccinations help stop the

together four different llama antibodies,

spread of the virus, but the shots

two against influenza A virus and

inoculate against only a handful of flu

two against influenza B virus. Wilson

strains. Because influenza mutates so

and Ward led the X-ray and electron

quickly, epidemiologists must race each

microscopy structural studies to show

year to predict the identity of the next flu

exactly where this four-in-one antibody

The Scripps Research

season’s major strains and then crank

was binding to influenza proteins.

team is developing

out a new vaccine accordingly. Even

“universal” approaches

then, the best matched vaccines are

“In this case, the llama antibodies could

only about 4 0 to 60 percent effective.

be easily linked together to create multi-

For certain types and strains of influenza

specific antibodies binding to different

could help prevent

A viruses, vaccine efficacy can drop to

sites on different targets,” Wilson says.

many more cases.

as low as 10 to 20 percent. The Scripps

“The multi-specificity was key to having

Research team made news recently

broad coverage of highly variable

for advances in helping develop an

pathogens like influenza.”

hospitalizations

to flu therapy that, if they prove effective in humans,

*Estimates by Centers for Disease Control and Prevention

experimental influenza therapy—with the help of llamas.

Their research showed that when administered a s an injection, the

Using a rare type of antibody produced

antibody could target v ulnerable sites

by the South American cousins of

on influenza A and B and protect mice

the camel, the Scripps Research

against lethal infections. When they

scientists and an international team

tested the multi-domain antibody, it prevented 59 strains of human and

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GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH

avian influenza A and B viruses from multiplying in the mice—an important first step in determining whether the influenza inhibitor could possibly work in people.

Working with scientists at the University of Pennsylvania, the team developed a different delivery mechanism, a “gene mist” containing viral vectors (harmless viruses used to deliver molecular payloads into the genome). When the mist was sprayed into the noses of mice, the vectors carried a genetic blueprint for the engineered antibody into cells of the animals’ respiratory systems.

Those cells, now containing the flufighting gene in their DNA, produced the antibody, confirming immunity to dangerous strains of flu.

If a similar strategy works in humans, an annual inoculation might still be required, but it would theoretically protect people against far more strains than the seasonal flu vaccine. “And there are other intriguing possible advantages,” Collins wrote of the new strategy.

“For example, the rapid protection this approach might afford, along with its potential to neutralize many forms of avian influenza, suggest it might be called into action to help quell an emerging flu pandemic far more swiftly than is possible with traditional vaccines.”

Until then, the team at Scripps Research is on the case.

The llama antibodies could be easily linked together to create multi-specific antibodies binding to different sites on different targets. In this case, the multi-specificity was key t o having broad coverage of highly variable pathogens like influenza.

Ian Wilson, DPhil Chair of the Department of Integrative Structural and Computational Biology at Scripps Research

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Science Changing Global Health

Matthias Pauthner, PhD, opened the internet browser on his laptop and there, snaking across the screen, was the heartbeat of a 4-year-old boy.

Pauthner sat at his small lab desk in La Jolla, California, surrounded by scientists working in white lab coats. The boy lay in a hospital bed in Sierra Leone, half a world away in West Africa, surrounded by nurses dressed head-to-toe in biosafety gear. The boy had Lassa fever, a disease that kills around 80 percent of the people who contract it. He was in the hot zone, fighting for his life.

A small white patch stuck to the boy’s chest connected the scientist in America and the young patient in Sierra Leone. Paired with a smartphone in the hospital where the boy was being cared for and where he was enrolled in a study of Lassa patients, the wireless heart monitor transmitted real time electrocardiogram readings of the boy’s heartbeat to a secure internet portal accessible to

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OUTSMARTING OUTBREAKS

Genomic detectives are hot on the trail of deadly viruses Scripps Research scientists work in outbreak zones to transform disease prevention, diagnosis and treatment

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Science Changing Global Health

the doctors and research team in Sierra Leone and to Pauthner and his colleagues in California.

“We were able to record a continuous ECG reading of his heart for five consecutive days, something that isn’t even regularly done for patients in the United States,” said Pauthner, several months after the boy was admitted to the hospital. “His temperature when he was first admitted was really high, and his heart rhythm erratic.

His heart stabilized the next day when his temperature came down. He lived, but it was touch and go initially.”

Pauthner is a postdoctoral researcher and part of a team of scientists at Scripps Research who study the life-and-death dance between humans and some of the world’s most dangerous viruses. Led by Kristian Andersen, PhD, an associate professor in the Department of Immunology and Microbiology at Scripps Research, the team has developed a unique system for studying pathogenic viruses, applying infectious disease genomics to track how viruses emerge and spread to cause large-scale outbreaks.

They combine this deep profiling of viruses with medical data gathered from patients to look for clues to why some pathogens are more virulent and why some people are better able to survive infections.

Top: Scripps Research's Kristian Andersen working with local researcher, Mambu Momoh, in Sierra Leone.

Bottom: Electron microscope image of Lassa virus.

Working with scientific collaborators around the globe, the team studies several dangerous viruses that have emerged in recent time. They include Lassa and Ebola viruses, highly lethal pathogens that cause viral hemorrhagic fevers, so named because the infection can cause blood vessels to rupture, resulting in severe internal and external bleeding. The Scripps Research team also focuses on Zika and West Nile, mosquito-borne viruses that were first identified in Africa but now plague other continents as well, including North America.

“We want to understand how these viruses travel so that we can improve early detection and predict how quickly a virus will spread,” says Andersen, who is also director of infectious disease genomics at Scripps Research Translational Institute. “Beyond that, our research aims to improve prevention, diagnosis and treatment of emerging viruses—whether they are known diseases or something we have yet to discover.”

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Kenema Government Hospital Field Site Sierra Leone

Lassa risk zone 2013-2016 Ebola outbreak

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Science Changing Global Health

Science in Sierra Leone The Lassa fever research program in Sierra Leone is a case study in the promise and challenges of studying emerging viruses. Kenema district was a flashpoint of the civil war that engulfed Sierra Leone from 1991 to 2002. The region is rich in alluvial diamonds, which were used to finance the brutal rebel group, the Revolutionary United Front. The war-torn country was dramatized as the backdrop for the 2006 movie Blood Diamond, which starred Leonardo DiCaprio. As the country has recovered from the long conflict that killed around 50,000 people and devastated its infrastructure, including its health systems, it has contended with multiple outbreaks of endemic disease.

Andersen and his team are part of the Viral Hemorrhagic Fever Consortium, an international collaboration of researchers studying Lassa and Ebola with the intention of reducing the number of infections and deaths caused by the viruses. The consortium conducts research with local scientists and doctors at a hospital site in Kenema, the country’s second-largest city and capital of the Eastern Province, known for having the highest incidence of Lassa in the world. People who contract Lassa and come to Kenema for treatment are admitted to the Lassa ward at the Kenema Government Hospital. The Kenema ward was also used to treat Ebola patients during the 2013-2016 Ebola epidemic in West Africa that infected 28,000 people and killed more than 10,000.

Building relationships with Sierra Leone’s government and local research staff has been critical to studying the viruses. Mambu Momoh, a medical laboratory scientific officer of Sierra Leone’s Ministry of Health and Sanitation who works at the Kenema Government Hospital Viral Hemorrhagic Laboratory, says collaborating with Scripps Research scientists has been instrumental in expanding local expertise and capacity to respond to outbreaks. He worked on the front lines of the 2013-2016 Ebola epidemic and his team diagnosed the first case in Sierra Leone using diagnostics developed and deployed by Andersen and his colleagues.

Photos clockwise from top left: An aging electrical generator for Kenema Government Hospital; Scripps Research scientists Raphaëlle Klitting, Kristian Andersen and Matthias Pauthner; Children in Sierra Leone learning about disease prevention; Research vehicle being prepared for Sierra Leone’s sometimes

“I have always enjoyed working alongside colleagues from the United States who are not only giving financial and logistic support to our site but also expertise and mentorship,” Momoh says. “It has been very inspirational for me, and I’ve gained much more experience in molecular biology science and gotten some high-tech training to enable us, the citizens, to carry out highly specialized scientific work in our lab.”

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rugged roads; Local research staff scientist works in the lab at Kenema Government Hospital.

Members of the Scripps Research team travel to Sierra Leone to work with Momoh and the other local staff on research projects. Pauthner has been to Kenema twice for field work, most recently for a month in January 2019. Many of the roads were muddy from the heavy rains and the trip from the international airport in Freetown, the country’s capital, to the Eastern Province was a rugged five-hour drive in a 4-wheel drive truck. During the trip, he stayed at a compound in Kenema maintained by the Viral Hemorrhagic Fever Consortium as a base of operations for local research staff and visiting scientists.

One of Pauthner’s tasks was to teach the nurses at the hospital to apply the heart monitor patches to Lassa patients and sync the monitors to smartphones to transmit data via the internet. The patches are a pilot study that feeds data directly to researchers in the United States. He also worked in the hospital’s Viral Hemorrhagic Laboratory processing samples, which required donning a biosafety gown, double gloves, headcover, boots and goggles. The air conditioner for the lab is notoriously unreliable.

“Once, I was suited up and the air conditioner went out,” Pauthner says.

“It got so hot I was soaked in sweat within minutes.”

Pauthner rode along on expeditions to villages in the Eastern Province where cases of Lassa had recently been reported. Lassa is transmitted from rodents to humans, typically when rats get into homes and infect food or when people eat the rodents. To prevent infections, local staff of Kenema Government Hospital travel to the villages to educate people on ways to avoid infections and unintentionally spreading viruses. Sierra Leone’s population is young, with about 42 percent under the age of 15, so the team piques their interest with popular African rap music and movies, then educates them on how to avoid infection.

The team also collected rats from the homes of people who caught Lassa to gather samples of viruses infecting the rodents. They collected blood samples from people in the villages who may have been recently exposed to infection. The blood samples are studied by the Center for Viral Systems Biology, a NIH-funded collaboration led by Andersen,

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Science Changing Global Health

that also includes Tulane University, University of California Los Angeles, MIT and Harvard Medical School. The center analyzes blood from survivors of past outbreaks of Lassa and Ebola to learn how they fought off the virus, merging computational analysis, machine learning and new technologies to discover how to minimize sickness and death in the future. One possible explanation for why some people fight off infections better than others is that they may produce special versions of immune system proteins, called human leukocyte antigens, that are particularly effective at recognizing infected cells. This would allow the immune system to more rapidly destroy infected cells, and hence clear the infection. Identifying and mimicking these highly

human toll. Generally considered to be a mild disease, when Zika virus infects pregnant women it can cause serious birth defects in babies, including smaller heads and brain damage.

First discovered in Africa in 1947, Zika was found in Brazil in September 2014. Using genomic analysis, Andersen’s team at Scripps Research determined that Zika circulated for more than a year and a half before being detected. From Brazil, a large outbreak spread throughout the Americas in 2015 and 2016, with 62 cases reported in travelers returning to the United States from affected areas in 2015, growing to more than 4,800 travel-related cases and 224 local mosquito-borne infections in the United States in 2016. The Scripps Research team also discovered that Zika entered Florida several times via travelers from the

effective variants could serve as the basis for developing new types of vaccines and antiviral drugs.

Caribbean before it was discovered. More recently, a genomics study of travel-associated Zika cases by Andersen’s team revealed an undiscovered outbreak in Cuba in 2017, underscoring the need for coordinated disease surveillance. This new field of “genomic epidemiology” will be critical to understanding and preventing future outbreaks.

Troublesome family trees In addition to deciphering what leads to different outcomes when humans become infected with a virus, the scientists also track how viruses spread. Similar to the way companies like Ancestry or 23andMe can trace a person’s ancestry by analyzing the DNA from a saliva sample, the Scripps Research team uses samples taken from various areas of Sierra Leone to create family histories of Lassa virus strains.

Genomic similarity between different virus strains can be used to track how fast and far viruses spread as well as how quickly they evolve.

Creating viral family trees isn’t just an academic exercise.

Deciphering what factors allow viruses to spread rapidly through and between host populations – whether rodents, insects or humans – is key to predicting and controlling future outbreaks. Some viruses move far more quickly than others. The global outbreak of swine flu in 2009, for example, took just six weeks to spread as widely as the typical seasonal flu travels in six months. First reported in Mexico, the flu rapidly spread around the globe, resulting in as many as 89 million cases and 18,000 deaths, according to the U.S. Centers for Disease Control and Prevention.

The rapid spread of Zika in the Americas is another case study of a virus taking a surprising turn and a severe

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Raphaëlle Klitting, PhD, another postdoctoral researcher on Andersen’s team, is attempting to explain why certain viral strains spread so aggressively. To do this, she uses skills honed as a graduate student at France’s Aix-Marseille University, where she studied yellow fever, an acute—and often fatal—viral disease transmitted by infected mosquitoes. Lassa virus is classified as a biosafety level 4 (BSL4) infectious agent, the most dangerous class, so working with the live virus in the United States requires an elaborate and expensive facility, including specially sealed rooms, pressurized protective suits and elaborate decontamination protocols. In the lab at Scripps Research, Klitting avoids the cost and hassle by working with what are called “surrogate systems,” safe noninfectious viruses modified to carry only a portion of the Lassa virus. Among other things, in recent experiments she has engineered surrogate viruses mounted with the molecular “key” Lassa uses to enter cells’ outer envelope. By swapping out different versions of the Lassa envelope, she tests their penetrating power.

“We want to know which variants are better at entering human cells versus rodent cells,” she says. “This could help us identify which strains are likely to jump from rats to humans or to spread from human to human. With this information, we can deploy

“Doing field work really made me a better scientist. You have to structure your research to work with the conditions you’re given. And it’s where you see what’s happening in real life, where the virus is spreading.”

– Raphaëlle Klitting, PhD

countermeasures and stop that from happening. You could also imagine at the beginning of an outbreak analyzing the virus to predict how fast it could transmit and by what means it could spread, which could help public health officials respond more effectively.”

During her first visit to Kenema at the peak of the dry season in January 2019, Klitting came to appreciate that conducting research in a laboratory in Sierra Leone presents a different set of challenges than in a La Jolla laboratory. To freeze safe, deactivated samples to ship outside Sierra Leone, the team needed liquid nitrogen, but the liquid nitrogen generator was struggling because the air conditioner couldn’t cool the room enough. Klitting and her colleagues were coaxing the machine to eke out just enough liquid nitrogen when their generator ran out of fuel and they had to wait days for a money wire to buy more.

“Doing field work really made me a better scientist,” she says. “You have to structure your research to work with the conditions you’re given. And it’s where you see what’s happening in real life, where the virus is spreading.”

She was also impressed with the bravery and skill of the hospital’s medical staff, many of who put themselves at risk caring for patients during past Lassa and Ebola outbreaks. Tragically, during the 20132016 Ebola epidemic, several of the hospital staff became infected and died from caring for patients.

“It’s remarkable how they stay motivated,” she says. “Some people are just heroes.”

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Calibr accelerates drug discovery.

A drug designed to treat leprosy was repurposed as an effective treatment for childhood diarrhea—a life-threatening illness—and delivered in record time, progressing from laboratory to clinical trial in only three years.

To overcome the barriers that slow the translation of new scientific discoveries to innovative medicines for patients, Scripps Research has created internal drug discovery and development capabilities. Calibr, an operating division, possesses the expertise and infrastructure (among its chemical libraries is the unique ReFRAME repurposing library) to bridge basic discoveries to innovative early preclinical drug discovery and human proof-of-concept clinical development, providing a framework for seamless integration of research and development activities.

These efforts have already produced a pipeline of innovative candidate medicines. Several drugs have entered human clinical trials, including a regenerative approach to osteoarthritis and treatments for tuberculosis and cryptosporidiosis. A significant drug discovery portfolio at Calibr

Scientists are engineering a longacting antibody that protects against neuroinflammation in patients with Parkinson's disease.

is focused on neglected tropical diseases that disproportionately affect global health in the developing world including tuberculosis, malaria, HIV, helminth infections, and diarrheal disease.

The challenges created by pathogen resistance and/or the lack of efficacy with current drugs, and limited access driven by cost-of-goods or lengthy treatment protocols, have been exacerbated by the slow development of effective new drugs. To meet these challenges, Calibr has partnered with the Bill and Melinda Gates Foundation to form an integrated drug discovery platform to identify and develop innovative approaches to new medicines for neglected diseases including tuberculosis, malaria, and HIV. We work closely with the Foundation to streamline efforts and accelerate drug discovery relevant to global health. Calibr will also be expanding these efforts as an anchor partner in the Wellcome Trust’s new Hub for Innovative Technologies for Neglected Tropical Diseases Flagship.

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When researchers found that isoxazolines, commonly used in veterinary products to protect pets from fleas and ticks, also killed disease -carrying mosquitoes, they identified a strategy to stem global outbreaks of malaria, Zika virus and potentially Lyme disease.

How does Calibr translate groundbreaking discoveries into lifesaving drugs?

Calibr, the drug discovery and development division of Scripps Research, was founded on the principle that new medicines can be created faster by pairing world-class biomedical research with advanced technologies and clinical expertise. Here’s a look at what makes Calibr different.

DIVERSE PIPELINE Calibr has created a broad therapeutic pipeline extending from early stage discovery through clinic-ready programs, including candidate medicines for cancers, osteoarthritis, Lyme disease and multiple sclerosis.

RESEARCH ALLIANCES Partnerships with organizations such as the Bill & Melinda Gates Foundation, Wellcome Trust, and the California Institute for Regenerative Medicine, and pharmaceutical companies like AbbVie extend Calibr’s capabilities and reach.

DEEP (LAB) BENCH The 72,000-square-foot facility houses state-of-the-art instrumentation and over 100 interdisciplinary scientists with decades of industry experience.

HIGH-THROUGHPUT ROBOTICS The institute’s robotics platform, built around technologies first developed in the auto industry, allows scientists to rapidly screen thousands of compounds to find new drug candidates.

DRUG REPURPOSING Calibr scientists built an extensive library of nearly all existing small-molecule drugs, called ReFRAME, to identify drugs that can be repurposed to treat major diseases.

CLINICAL TRIALS Calibr scientists conduct first-in-human clinical trials of promising therapeutic candidates, applying their deep expertise to advance therapies from the lab to the clinic.

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