By Allyson Mann
Avoiding the flu can seem like playing a game of chance, where the consequences of losing are sheer misery.
The symptoms—fever, sore throat, nasal congestion, cough, muscle aches, headaches, fatigue, vomiting and diarrhea—are unpleasant enough. But there can also be more serious repercussions. As of March, the Centers for Disease Control and Prevention reported nearly 25,000 flu-related hospitalizations and 128 pediatric deaths for the 2017–18 season.
Getting a seasonal flu vaccine might help, but it might not. Despite the best efforts of public health officials, the flu vaccine’s effectiveness varies year to year, and this season’s has not performed well. The CDC estimated its effectiveness at a mere 36 percent overall for the several strains of the virus it covers.
Ted Ross wants to improve the odds by building a better vaccine—one that will protect against any version of the virus. The UGA professor and Georgia Research Alliance Eminent Scholar of Infectious Diseases feels a sense of urgency. One hundred years after the Spanish flu pandemic killed an estimated 50 million people globally, the world health community is still not ready for the next occurrence, according to Ross.
“We didn’t make a lot of improvements in 100 years, and I don’t think we’re any more prepared for the next pandemic that comes along,” he says. “There will be another pandemic. It’s inevitable.”
A 1997 influenza outbreak in Hong Kong did not lead to a pandemic, though some feared it might. It started with the death of Lam Hoi-ka, a 3-year-old boy who tested positive for an unknown strain of influenza. Saliva samples were sent to laboratories all over the world, including the CDC, and a Dutch virologist identified the strain as H5N1, previously known only to infect poultry and wild birds. Authorities ordered the slaughter of every chicken—more than 1.5 million—in Hong Kong. By the end of the year, 18 people had been infected and six had died
“It was the first evidence that birds could directly give humans influenza,” Ross says. “Usually you have to go through an intermediary, like pigs, to adapt it to humans.”
At the time, Ross was a postdoctoral researcher at Emory University’s Vaccine Center, which received some of the Lam Hoi-ka samples through the CDC, which was seeking help solving the mystery. He had been focused on HIV and AIDS, but like many other scientists, he redirected his attention to try and understand why that particular virus was so deadly.
After Ross established his own laboratory—first at East Carolina University, then the University of Pittsburgh, and later the Vaccine and Gene Therapy Institute of Florida—he found that flu kept getting more of his attention and funding. When H5N1 re-emerged in the mid 2000s, he asked his grad students to consider how they could combat the new sub-types of influenza that continued to emerge.
“How do you make an effective vaccine if you’re constantly playing catch up, and you never know what’s coming?” Ross says. “We wanted to come up with a vaccine strategy where it wouldn’t matter what version of the flu came along—we’d have a vaccine on the shelf ready to use. At the time we were thinking only of H5N1, but without knowing it, we were talking about developing a universal vaccine.”
Ross is still pursuing that goal. In 2015, he joined UGA as director of the new Center for Vaccines and Immunology (CVI), where researchers work to expand their understanding of the immunology of infectious diseases and how vaccines work in different populations.
“A lot of times we make a vaccine and it’s effective, but we don’t understand the mechanisms of exactly why it’s working,” he says. “The better we understand how a vaccine operates in a human, the more we can apply that knowledge to other pathogens.”
CVI researchers are working to address not just influenza, but a variety of other pathogens, including dengue, Zika, Ebola, chikungunya, HIV and respiratory syncytial virus. And they’re making progress. In 2016, Ross and research partner Sanofi Pasteur announced the development of a vaccine that protects against multiple strains of H1N1 influenza in animal models. H1N1 caused a worldwide pandemic in 2009, when it was known as swine flu, but now it circulates as a seasonal form of influenza.
A year later, Ross and Sanofi Pasteur announced that they had developed a vaccine that protects against multiple strains of H3N2 influenza. H3N2 is the most predominant seasonal flu in circulation, and the CDC estimates this season’s vaccine effectiveness at only 25 percent for that particular strain. Ross’s vaccine has been tested successfully in animal models, and clinical trials are planned for 2019.
“It’s time to put this vaccine into people’s arms,” Ross says. “We need to find out if their immune responses mimic what we found in animals.”
The term universal flu vaccine has shown up in numerous headlines this year—in coverage of vaccine effectiveness, discussions of when the flu season peaked and reports on U.S. senators who called for a $1 billion federal investment in vaccine research.
Ross, however, prefers the term broadly protective. Universal implies that every single version of influenza will be protected with a single vaccine, he says.
“That’s a high bar and not realistic, at least in my lifetime,” he says. “We need to target the major subtypes of influenza and come up with a vaccine that recognizes all of the strains within those subtypes. It may take more than one vaccine, but at least we’ll have something that’s broadly protective against most of the versions that infect humans.”
Only a few strains of flu virus circulate worldwide in a typical year, but dozens more may exist. There are several types of influenza; the most problematic is influenza A because it travels the world among birds, pigs and humans. The avian strains don’t easily infect people, but the virus is constantly mutating and swapping genes with other influenza viruses it encounters—and sometimes these genetic changes create a version that allows an avian or swine flu to move into humans. The avian flu strain H7N9, for example, moved into humans in China in 2013 and has since infected more than 1,500 people.
Strains of influenza A are distinguished according to the combination of proteins on the surface of the virus. Hemagglutinin (H) attaches to cells to launch an infection, and neuraminidase (N) helps spread the virus once infection has occurred. Hemagglutinin has 18 subtypes, and neuraminidase has 11 subtypes. So H3N2, for example, indicates a strain with the H3 subtype of hemagglutinin and the N2 subtype of neuraminidase.
Ross describes the flu virus as looking like a flower with a stalk and a globular head. Most traditional flu vaccines target the head of the flower, stimulating the immune system to generate antibodies that bind to the hemagglutinin and prevent the virus from entering a cell. If the head changes, the vaccine is no longer effective.
Often, that’s what happens. U.S. health officials decide what to target based on which strains are circulating. Unfortunately, it takes six months to manufacture and deliver the vaccine. During that time, when flu is circulating in the southern hemisphere, the virus can mutate into a form that is not susceptible to the new vaccine.
It’s this lack of resilience in the vaccine that Ross wants to change. He uses a deck of cards—with each suit representing different subtypes of influenza—to describe his approach to creating a broadly protective vaccine. Rather than choosing one card and using it as the basis for a vaccine, he stacks the deck in his favor by using them all.
“We take little bits and pieces of every card, and we make a new card,” he says. “There’s a little bit of every single one of those flu strains in a single vaccine. That way it doesn’t matter what virus you see in the future, because you have immunity already to any version that’s in the deck.”
Using a data technique called COBRA—Computationally Optimized Broadly Reactive Antigen—Ross and his team are taking hemagglutinin mutations from every flu strain that has ever circulated and weighting them equally to create their vaccine. COBRA allows the researchers to make sure that even minor strains are represented in the final version. The vaccine thus provides the immune system with the information needed to generate antibodies when exposed to any variant of the flu virus.
“If you get the current vaccine but are exposed to a variant, it doesn’t help,” Ross says. “With our vaccine, you’ll have immunity no matter which strain you’re exposed to.”
A more flexible vaccine could be manufactured year-round, instead of just seasonally. It could be stockpiled and better distributed to people worldwide, where it would be ready for an outbreak. The vaccine would still need to be modified as new influenza strains emerge, but there’s a lot to gain, Ross says.
“If we can get in a situation where we only update the vaccine every decade, that’s an enormous improvement over how we do flu vaccines now.”
The bad news, according to Ross, is that flu will not be eradicated.
“We won’t get rid of flu as long as we have birds on the planet,” he says. “Flu infects almost every species, and its reservoir is waterfowl—birds that fly all over, allowing the virus to mutate. We’ll always have mixing going on, and then a new version will come back to people.”
The good news is that medical technology has been able to ameliorate some of the symptoms, keeping people alive. The 1968 H3N2 pandemic wasn’t as bad as the 1957 H2N2 pandemic, and 1957 wasn’t as bad as the catastrophic H1N1 pandemic of 1918.
Exposure to strains like these—especially if it’s the first infection—influences how the immune system responds to the flu vaccine, according to research by Ross and Sanofi Pasteur. After volunteers received a flu vaccine, Ross and his team monitored the ability of the vaccine-generated antibodies to neutralize a wide variety of influenza viruses over four years.
They found that older people had a broader immunity to older influenza strains thanks to years of exposure through either vaccination or natural infection, but they were susceptible to newer strains. Younger people had immunity that could effectively fight the newer viruses, but they typically did not react to the historical strains as well as their elders. That difference, and others, should be taken into account when creating a vaccine, Ross says.
“The vaccine has to work for people of all ages, people in developing countries as well as places where people have access to medical care, pregnant women, people with compromised immune systems, and people of different genetic backgrounds,” he says. “It’s a little unrealistic to think that there’s going to be one vaccine for everyone.”
Ross envisions a series of designer vaccines, allowing health care professionals to choose the version that will work best based on a person’s background, including factors like genetics and medical conditions.
To that end, he’s collaborating with UGA researchers like Katie Erlich, assistant professor of psychology. Erlich is examining how stressors such as abuse or malnutrition affect response to a vaccine. Ross is also collaborating with Glen Nowak, professor of advertising and public relations, who’s investigating the reasons why people resist getting vaccines.
The 2019 clinical trials planned by Sanofi Pasteur will assess the effectiveness of Ross’s H3N2 vaccine, but Ross also hopes to conduct trials of his own in Athens. He wants answers to secondary scientific questions that will aid him in his quest to create the most effective vaccine for influenza—and perhaps influence efforts on the other viruses being addressed at the Center for Vaccines and Immunology.
This October, as president-elect of the International Society for Vaccines, Ross will co-chair the organization’s annual meeting in Atlanta. By then, the next flu season will be underway. Seasonal flu shots of varying effectiveness will be available, and the CDC will once again be tracking rates of disease, hospitalization and death. Ross will perhaps be turning his attention to creating a vaccine for influenza B, the “ugly stepchild” that has a lower incidence in humans, but is just as deadly. Influenza will be back in the headlines, and there will be more interviews and opportunities for Ross to discuss his approach to creating a broadly protective vaccine.
“Working on flu,” he says, “you get free publicity every winter.”
Center for Vaccines and Immunology
Established in 2015, the CVI brings investigators focused on vaccine development and immunology under one roof where they study a variety of pathogens. Leveraging the university’s expertise in infectious disease, veterinary medicine, ecology and public health, CVI investigators focus on translational studies to test and assess the efficacy of vaccines and immunotherapies in development by industry, government and academic institutions. For more information, visit vet.uga.edu/cvi.