More than 200 years ago, British physician Edward Jenner changed the history of medicine when he inoculated a 13-year-old boy with vaccinia virus (cowpox) and demonstrated immunity to smallpox in 1796. Suddenly, there was a powerful new weapon in the long-standing war between humankind and disease-causing viruses. In the centuries since, millions of lives have been saved by vaccines against pathogens like smallpox, polio, and measles. However, for all the advances in vaccine science and all the success stories, some viruses have remained hard to vanquish—influenza and human immunodeficiency virus (HIV) among them.

That is rapidly changing. Scientists have a greater understanding of how to arm the human immune system against viruses, as well as new technology for creating vaccines at a speed that would have been unimaginable just a decade ago. In the shadow of Operation Warp Speed, which successfully developed, tested, and rolled out safe and effective COVID-19 vaccines in less than a year, vaccines are yet again poised to enter a new era.

At UAB, researchers and clinicians have developed and studied vaccines for decades; their work contributed to numerous vaccines on the market today. Now, they are embracing the latest science to forge ahead with new vaccines, working to make existing vaccines even better, and helping ensure that people everywhere have knowledge of and access to vaccines.

“There are a lot of people on this campus with expertise in vaccines, from the very basic science to the most translational,” says Frances Lund, Ph.D., former Charles H. McCauley Chair of Microbiology and founding director of UAB’s Immunology Institute. “Vaccines are something we are all very passionate about. They have enabled humanity to have a healthy lifespan that we could not have without them.”

Frances Lund, Ph.D.

The Covid Effect

Lund has long studied B cells, the immune cells that produce antibodies against viruses, bacteria, and other foreign particles that enter the human body. She is particularly interested in how to develop vaccines that ensure long-lasting, effective B cells throughout the body, not just in the lymph nodes. Her research—mostly on influenza—has answered numerous questions about how B cells develop, mature, and fight pathogens. She has also shed light on the importance and effectiveness of B cells in the lining of the lungs, the first place that respiratory viruses usually infect.

When COVID-19 emerged, Lund and colleagues, including Troy Randall, Ph.D., who holds The Meyer Foundation William J. Koopman Endowed Professorship in Rheumatology and Immunology at UAB, quickly pivoted to studying the SARS-CoV-2 virus. They launched a collaboration with Altimmune Inc., first carrying out basic research to discover which antibodies against the virus were most effective, and then helping develop an intranasal spray vaccine candidate, which their research suggested could lead to strong antibodies in the lining of the nose and airways.

“When you get a flu or COVID vaccine in your arm, you develop what we call systemic immunity, and this means antibodies in your lymph nodes and spleen,” says Lund. “What would be even better is B cells and specific kinds of secretory antibodies ready and waiting in your respiratory tract.”

Work on the Altimmune COVID-19 vaccine was halted in 2021 but, in the same way that lessons from influenza helped make COVID-19 vaccines possible, the lessons learned and technology developed from the pandemic are now leading to new possibilities when it comes to influenza.

For influenza, Lund explains, the challenge in creating an effective vaccine is keeping up with the fast pace at which the virus mutates and evolves. In the past, flu shots have relied on inactivated copies of the influenza virus or isolated proteins. Both take about nine months to produce and distribute and include protection against four strains of the flu at once.

Most of the COVID-19 vaccines currently on the market use a different, new technology called mRNA. Rather than provide the body directly with a piece of a virus to teach the immune system to recognize it, a strand of mRNA instructs the body on how to make these proteins itself. One of the advantages of the technology is it is much quicker to produce mRNA than whole viruses or even proteins.

“If we shift to mRNA vaccines for flu, this means is we can wait until much closer to the flu season to see what’s actually circulating and start designing vaccines,” Lund says. “I think this will lead to much better protection against any given season’s flu strains.”

Also, mRNA lets researchers combine many more viral proteins into one vaccine. This could also help provide better protection for any given flu season, when numerous strains of influenza might circulate at once.

“I think the next low-hanging fruit we’re going to see with the flu vaccine is combo-vaccines that can cover more strains,” Lund says.

Lund’s own research group is continuing their work on nasal vaccines and how to make sure B cells can produce anti-influenza antibodies that are long-lasting and found in the right place in the body. The results of their basic work, she says, will help inform future flu vaccines.

Paul Goepfert, M.D.

Pandemic Lessons

If the speed of creating mRNA vaccines is a boon for fighting influenza, it is also an incredible benefit in the race to develop a vaccine against human immunodeficiency virus (HIV), one of the fastest mutating viruses scientists have ever studied.  

“COVID is definitely a lower bar for vaccination than HIV,” says Paul Goepfert, M.D, professor of medicine and director of the Alabama Vaccine Research Clinic, housed at the Heersink School of Medicine. “With COVID, there are a handful of strains out there at once; with HIV there are thousands of strains and every single one of them can cause AIDS.”

While mRNA vaccines were being studied before the advent of COVID-19, the pandemic sped along their development and helped push the technology to maturity. With the new ability to develop mRNA vaccines at a record pace, Goepfert and colleagues have already launched a phase 1 clinical trial of an mRNA-based HIV vaccine at UAB—one of 10 sites nationwide. The idea behind the trial is that, with mRNA, many different vaccines can be rapidly developed and tested for their ability to elicit powerful anti-HIV antibodies in people.

“mRNA technology won’t magically give us a vaccine against HIV, but it’s going to help hugely in HIV vaccine development,” says Goepfert. “We can develop many more vaccines in succession and if one doesn’t work, we can quickly go back to the drawing board.”

Goepfert and other researchers will test whether people who receive each experimental vaccine generate antibodies that are capable of recognizing many different strains of HIV at once—moving in the direction of a universal HIV vaccine. Scientists have already identified some of these “broadly neutralizing antibodies” but need to determine which vaccines can coax the immune system to generate them.

“Historically, vaccines were just versions of a virus, because we didn’t know any better,” says Goepfert. “Now, we’re getting better and better at tuning the immune response to be much more specific, effective, and safe.”

Warner Huh, M.D.

Canceling Cervical Cancer

While the development of an HIV vaccine has, for the past few decades, been frustratingly slow, the human papillomavirus (HPV) vaccine is a modern-day success story. Scientists have known for decades that long-lasting HPV infections not only cause most cases of cervical cancer, but also boost the risk of a person developing other cancers. The 2006 approval of Gardasil, the first HPV vaccine, was the first time a vaccine had been produced
to help combat cancer.

“We are now starting to see a significant drop in the rate of pre-invasive disease and, perhaps, cancer rates,” says Warner Huh, M.D., chair of the Department of Obstetrics and Gynecology, who helped lead some of the earliest tests of Gardasil. “We’re no longer in a place where we can just dream about a world with no cervical cancer, we’re actually seeing that this is highly realistic and probable.”

In the 15 years since Gardasil’s approval, Huh and other scientists have continued to study the safety and effectiveness of the vaccine. In 2016, the U.S. Food and Drug Administration approved a two-dose schedule instead of three. Now, Huh is spearheading efforts to develop an HPV vaccine that doesn’t need refrigeration.

“Cervical cancer is a major issue in the developing world and if we can figure out a way to give one shot to individuals, that would be a massive step in the right direction,” he says.

He and others at UAB are also modeling rates of HPV vaccination, cervical cancer screening, and cancer cases to determine when cancer screening—in the form of Pap smears and HPV tests—is no longer needed. “This is such an incredibly effective vaccine that we might be able to tell the next generation of women that they’re fully protected against cervical cancer and may not even need screening, which would be amazing,” he says.

Wendy Landier, Ph.D., CRNP

A Communication Strategy

The HPV vaccine, though, is also an example of the continued challenges of rolling out a vaccine. Misinformation about the risks and benefits of vaccination has slowed rates of vaccine uptake, and the pandemic only exacerbated rates of vaccine hesitancy, most research suggests.

“The divisiveness of the COVID vaccine and its rollout had this halo effect on other vaccines that we give,” says Huh.

Wendy Landier, Ph.D., CRNP, a professor of pediatric hematology-oncology, is well-armed to tackle some of these challenges. Since the release of the HPV vaccine, she and colleagues have been studying issues surrounding the vaccine, including its safety and ability to provoke an immune response, as well as the uptake of the vaccine, in one unique population: childhood cancer survivors.

Survivors of childhood cancers are at increased risk of developing HPV-related cancers in the future, but also have low rates of HPV vaccination. In 2021, Landier’s team became the first to report that HPV vaccines are safe in these patients and provide similar levels of immunity as those seen in healthy young people. They also showed that the reason many cancer survivors don’t get the vaccine is simply because a health care provider doesn’t bring it up.

“In young cancer survivors, routine preventive care may fall through the cracks because everyone is very focused on cancer recovery,” says Landier.

With that in mind, she is now working on communications strategies to ensure that pediatric oncologists start integrating HPV vaccine recommendations into their routine cancer follow-up visits. The intervention has been rolled out at six sites already and Landier and her collaborators are tracking how it helps boost vaccine uptake among childhood cancer survivors.

“Vaccines are something that people are talking about in a way they’ve never done before,” she says. “That can be both helpful and challenging.”

Other UAB researchers have similar sentiments—as they forge ahead with a new generation of safe and effective vaccines, they hope their passion and messaging reach the public.

“Hundreds of years ago, in the absence of vaccines, infections were the number one killer of children,” says Lund. “They’ve improved human health so much and we’re still working on improving things even more.” – Sarah Williams