It’s long been known that the vaccine against the human papilloma virus offers protection when administered to those who’d never experienced HPV infection. But new research suggests the possibility that it could also help those who’d been previously infected to guard against re-infection, according to results recently published in EBioMedicine.
Vaccines are designed to create immunity, also known as immune memory, to keep infection at bay. Researchers at Fred Hutchinson Cancer Research Center have found that the HPV vaccine helps the immune system “remember” the virus better than natural HPV infection itself. A single dose of the vaccine appears to improve immune memory in those previously infected with HPV, raising the possibility that the vaccine could help prevent re-infection.
Until now, whether the vaccine could benefit those who had already experienced HPV infection was unknown, said senior author Dr. Denise Galloway, a virologist at Fred Hutch whose work linking HPV to cervical cancer and development of virus-like particles helped pave the way to the vaccine.
“We wondered if we gave [previously infected individuals] vaccine, could you boost that immunity?” said Galloway. “And the answer to that was definitely yes.”
A memorable vaccine
There are currently three approved vaccines against cancer-causing strains of HPV, covering from two to nine different strains of the virus. The standard vaccination schedule, approved for women between the ages of nine and 26 and men from nine to 21, calls for three doses. But whether all three doses are necessary to trigger an immune response and prevent infection is currently under investigation, including by Galloway and her team. A one- or two-dose schedule could help reduce vaccination costs and improve adherence.
Our immune systems are designed to remember, taking advantage of a first infection to lay the groundwork for better pathogen recognition and quicker response the second time a microbe comes knocking. A complex network of “trained” immune cells and specialized proteins work together to provide immunity once an infection has occurred. Vaccines are designed to recreate this process and produce immune memory in the absence of an actual infection.
But not all memories are created equal, and not all viruses produce equally strong — and equally protective — memories. While the HPV vaccine initiates powerful immune responses, not much was known about whether natural infection with HPV would churn out a generous number of gimlet-eyed immune sentries — or a skeleton crew that could be overwhelmed by a second assault. Previous work suggested the second outcome was more likely. Galloway and first author Dr. Erin Scherer aimed to clarify the outcome of natural HPV infection and also discover what effect a single dose of the HPV vaccine might have.
They focused on B cells, the type of immune cell that produces antibodies, proteins that circulate through our system and act as natural blocks to viral entry into target cells. Memory B cells — which arise after infection and are capable of a faster, stronger response to a second encounter with a pathogen — can be identified by hallmark changes in their DNA and a different spectrum of proteins on their surface. When memory B cells encounter the pathogen they’ve been trained to recognize, they race to respond, expanding in number and leading to a huge increase in the amount of anti-pathogen antibodies.
Scherer examined antibodies and memory B cells that recognize HPV16, one of the major cancer-causing strains of HPV that is included in all the approved HPV vaccines. In a pilot study, she looked in blood samples from 10 women between the ages of 27 and 45 who had detectable levels of antibodies against HPV16 — a sign of prior infection. Five of the women were given one dose of the quadrivalent HPV vaccine and five remained unvaccinated. Blood samples were taken prior to vaccination, one week after, and then one month and six months after.
The researchers found that in most of the individuals, vaccination increased the quantity and quality of HPV immunity. Levels of antibodies against HPV16 in four of the vaccinated individuals increased, an average of 77-fold.
“With a single dose of vaccine, there was a huge boost in the amount of antibody and a huge boost in the number of memory B cells,” said Galloway.
Vaccination also improved the ability of antibodies to block infection of target cells by HPV — a critical quality known as neutralization. During the course of an infection, B cells undergo a process to refine the ability of their antibodies to bind to, and neutralize, the target pathogen. In order to examine how well the HPV vaccine prompted B cells to refine their antibodies, Scherer and Galloway recreated antibodies using genes from anti-HPV memory B cells.
They found that the antibodies occurring in natural infection were poorly neutralizing. Fewer than 10 percent could neutralize HPV, “and the ones that did were not great,” said Galloway.
In contrast, all the anti-HPV16 antibodies the scientists found “after one dose of vaccine were pretty potently neutralizing,” she said. Additionally, vaccination increased the frequency of memory B cells recognizing HPV16 up to 26 times.
Scherer and Galloway also learned more about the variable, but generally weak, immune memory that HPV usually generates. Only two of the vaccinated women showed signs that natural infection had produced enough memory B cells to trigger a characteristic “memory” response. In two more, natural infection had produced so few memory B cells that the vaccine particles appeared to be encountering, and stimulating, new B cells that had never before responded to HPV.
Together, the results suggest that natural HPV infection does not lay a strong bulwark against re-infection and that vaccination can turbo-charge some of the key components of protective immunity even in individuals who have been previously infected.
More to learn
Galloway’s team has only shed light on immune memory during a short window after vaccination. They are now looking over time to see how post-vaccination, anti-HPV memory changes or improves, and whether one, two or three doses affect memory differently.
Galloway doesn’t recommend that people already infected with HPV rush to get vaccinated. For one thing, vaccination won’t help anyone with an active infection clear the virus faster. And while the results suggest a potential benefit to immunity, the study wasn’t designed to demonstrate that vaccination can prevent disease in those previously exposed to HPV.
“You would have to show that that was really true before you could say that it’s really worthwhile” to vaccinate outside the currently approved age ranges, she said. While there may be specialized circumstances in which vaccination might be warranted, such as in cases of transplant where an individual’s immune system will be suppressed or if they expect exposure to new infections, current knowledge doesn’t support general vaccination for older individuals.
First and foremost, the study “says how potent a single dose [of vaccine] is,” Galloway said.
Sabrina Richards is a staff writer at Fred Hutchinson Cancer Research Center. She has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
