Starting in 2014, an Ebola virus epidemic swept through West Africa, killing 11,325 over two and a half years.
This hemorrhagic fever stayed mostly in Africa, but panic spread quickly to the United States after a Liberian man visiting relatives in Dallas died from the disease in September 2014, and two nurses fell ill. The workers fully recovered, and there was only a remote chance the virus could spread. But health officials had to reassure Americans repeatedly that the U.S. was not on the verge of an Ebola outbreak.
Ironically, at the time there were two Ebola vaccines that could have stopped the epidemic before it started. One had been under development for more than a decade prior to the 2014 outbreak. Neither vaccine was used until the end of the epidemic in 2016.
The Ebola vaccine’s slow emergence into clinical use is not unique. Prototype vaccines already exist for Zika, chikungunya, West Nile virus, and several other rare but serious illnesses that are established in Texas, most of them vector-borne. Like Ebola, they tend to be most prevalent in poor countries that don’t have the resources to fight them effectively.
But for reasons tied to financing and stringent rules on producing vaccines, these potentially life-saving drugs become so-called “orphan vaccines,” left nowhere near ready to protect vulnerable populations.
“There’s not a lot of interest, I would say, in orphan vaccines in the same way that we’ve developed interest in [orphan] drugs that are for very rare conditions,” said Trish Perl, MD, chief of the division of infectious diseases at UT Southwestern Medical School in Dallas and a member of the Texas Medical Association’s Committee on Infectious Diseases.
On the other hand, some physicians question whether vaccines are the most immediately effective solution for fighting these types of diseases.
“There’s a sense that if we just had enough money to get this vaccine out there, everything would be fine. It’s much more complex,” said Jane Siegel, MD, a pediatric infectious disease specialist and former chair of TMA’s Committee on Infectious Diseases.
However, the need to combat these diseases remains clear, says Peter Hotez, MD, co-director of the Texas Children’s Hospital Center for Vaccine Development (CVD) in Houston, a nonprofit that produces vaccines for neglected tropical diseases. Texas — with its growing, dynamic population and its warm climate — has proven to be a great breeding ground for such illnesses, he says. (See “Swat Team,” June 2018 Texas Medicine, www.texmed.org/SwatTeam.)
“When we started [Texas Children’s CVD], we were focused on vaccines for Asia, Africa, and Latin America,” said Dr. Hotez, who also directs the National School of Tropical Medicine at the Baylor College of Medicine in Houston. “But now … we realized that there’s a serious problem with tropical diseases right here in Texas.”
License to heal
Every vaccine used in the U.S. requires a license from the Food and Drug Administration (FDA). The steps to obtain that license are designed to be thorough to ensure safety, but that also makes them expensive to complete. (See “Stages of Vaccine Development,” page 44.)
Governments in the U.S. and Europe require extensive laboratory and clinical testing before a vaccine is approved, both difficult and costly processes, says Dr. Perl. Pharmaceutical companies are understandably reluctant to pick up the tab unless they are sure of a return on investment. And while U.S. government programs fund production of drugs that treat, say, a rare form of cancer, there are no comparable programs designed to produce and test vaccines for diseases that afflict a small but significant number of people.
The most frequent bottleneck takes place in the Phase 3 human trials of the clinical development stage, says Scott Weaver, PhD, principal investigator for the Western Gulf Center of Excellence for Vector-Borne Diseases and director of the Institute for Human Infections and Immunity at The University of Texas Medical Branch at Galveston.
“That’s where it tends to become very challenging,” he said.
Phase 3 presents several problems that can be costly to solve: The first involves conducting the right kind of study on the right population. For a mosquito-borne illness like Zika, it would require finding a population that is vulnerable to infection in an area where the Zika-carrying mosquito lives. It would then require administering the vaccine to one group of people while administering a placebo to another group and then comparing results, Dr. Weaver says.
“If it’s a disease that’s very predictable [about when it strikes], you can often do that with small numbers of people at a pretty low cost,” Dr. Weaver said. “But if it’s a disease that’s unpredictable or that’s already [infected large parts of the population] — and both of those are true for Zika and chikungunya — then it becomes very difficult to even find the right place, and to estimate the number of people you’d have to vaccinate and then estimate the cost for doing a Phase 3 trial.”
Tracking the sporadic nature of these diseases, which can disappear as quickly as they appear, and the populations they affect, contribute to Phase 3 trials’ enormous price tags — easily hundreds of millions of dollars. For the most part, only two institutions have that kind of cash: large pharmaceutical companies and the U.S. government, Dr. Weaver says.
“Even if a big pharma company does an analysis and thinks there’s a big potential market for a vaccine, if they don’t know how much it’s going to cost [because it’s so hard to find the right test population] to successfully complete a Phase 3 trial, that uncertainty makes it very difficult to invest,” Dr. Weaver said.
Early stages of vaccine development, like animal testing, are often funded by the federal government though the National Institutes of Health (NIH). But Phase 3 trials are well beyond the NIH budget, Dr. Weaver said.
Generally speaking, the U.S. government does not fund the full costs of product and clinical development, including Phase 3 trials, unless there is a national defense issue, Dr. Hotez says. For instance, the Texas Children’s CVD is developing and testing a vaccine for leishmaniasis. Because it’s a parasitic disease affecting U.S. troops in Afghanistan, the U.S. Department of Defense is helping to support early development, he says.
Texas Children’s CVD also is developing a vaccine for another neglected parasitic disease, schistosomiasis, with NIH support, as well as a vaccine for human hookworm, with funding from the European Union and NIH.
But the center is one of just three nonprofit product-development partnerships worldwide working to develop vaccines using both private and public dollars. It is working on vaccines for five other diseases — Chagas disease, river blindness, arbovirus infections, and two corona virus infections: severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).
“These are the diseases that the big pharmaceutical companies are not in a position to make [vaccines for] because there’s no obvious financial return on the investment,” Dr. Hotez said. “Aside from those diseases that threaten U.S. troops deployed overseas, they are poverty-related diseases. These are people who are in extreme poverty who are primarily affected by them.”
Because they are diseases that mostly affect poor countries, there is less interest in addressing them in the wealthy countries that can afford to make vaccines, Dr. Hotez says.
However, these diseases of poverty are increasingly becoming a problem in Texas, he says. For instance, the center’s Chagas vaccine, which is about to go into clinical use, will likely be needed in Texas because of the disease’s steady presence here. Leishmaniasis also has emerged in Texas, so it might also be needed here one day as well.
But some doctors are concerned that focusing too heavily on vaccines could detract from tools that are more immediately effective and available for combatting these mostly vector-borne illnesses.
Spending hundreds of millions of dollars on a vaccine that has to be administered to an already hard-to-reach group of people may not be best use of limited funds, Dr. Siegel says.
“How hard is it going to be to get vaccines to the populations who would benefit?” she asked. “It’s going to be very hard. I’m a big vaccine champion, but I think there are different ways of preventing infections, and we have to look at all of those ways and weigh the pros and cons.”
For example, public health officials in the U.S. should look first at improving methods of vector control, Dr. Siegel says. She points to a study cited in the CDC’s Morbidity and Mortality Weekly Report for May 4, 2018, that says 84 percent of the 1,083 local mosquito control organizations in the U.S. were deficient in some way. Dr. Siegel says fixing those programs would provide a lot more bang for the buck in fighting Zika virus, chikungunya, and other mosquito-borne infectious diseases than vaccines.
Public health officials also should partner to determine which vaccines should be developed, Dr. Siegel says. Those officials have the best sense for which ones are most needed and can be delivered most effectively to their target populations.
Catherine Eppes, MD, another member of TMA’s Committee on Infectious Diseases, agrees that vaccine development may not always be the No. 1 health priority. But it remains a high priority, and the experience with Ebola shows why.
Just five months ago, an Ebola outbreak in the Democratic Republic of the Congo threatened to repeat the 2014 experience. But this time, an experimental vaccine produced by Merck and tested in the 2014 outbreak was given to 3,300 people. That, along with a rapid health care response, caused the World Health Organization to declare the outbreak over in July after the disease killed 33 people.
The country saw a second outbreak right on the heels of the first, and, again, the vaccine was a major tool in combatting it.
“At the end of the day, it means that a vaccine has huge benefits in many locations, but maybe not all,” Dr. Eppes said.
There are obvious limits on funding from any source, including the government, she says. But to avoid wasting the life-saving potential of new vaccines, medical professionals, pharmaceutical companies, and public health officials need to find more creative funding sources — like nonprofits — and pressure for more government support.
“It will require dedicated [public] funding and attention,” Dr. Eppes said, “and a lot of motivated people making sure it reaches the right priorities.”
Stages of Vaccine Development
Exploratory stage — Basic laboratory research to investigate vaccine candidates.
Pre-clinical stage — Use of tissue and cell cultures and animal testing to gauge the safety of a potential vaccine as well as its ability to provoke an immune response.
- Phase 1 — Small groups of people receive the trial vaccine to test its safety.
- Phase 2 — The vaccine is given to a larger group of people who have characteristics (such as age and physical health) similar to those for whom the new vaccine is intended.
- Phase 3 — The vaccine is given to thousands of people to test its efficacy and safety.
Regulatory review and approval — The drugmaker submits a license application and the U.S. Food and Drug Administration (FDA) inspects the factory where the vaccine will be made.
Manufacturing and quality control — The FDA and Centers for Disease Control and Prevention continue to monitor the production of the vaccine.
Sources: Centers for Disease Control and Prevention; Western Gulf Center of Excellence for Vector-Borne Diseases at The University of Texas Medical Branch at Galveston; The College of Physicians of Philadelphia
Tex Med. 2018;114(9):28-30
September 2018 Texas Medicine Contents
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