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University of Southern California Researchers Develop Vaccine That Boosts Immunity and Helps Patients Avoid Deadly Infections While in Hospitals

New vaccine could give clinical laboratories and antimicrobial stewardship programs the tool they need to dramatically reduce hospital-acquired infections

Healthcare providers and clinical laboratories continue to struggle against hospital-acquired infections (HAIs) and ever-evolving antimicrobial resistant (AMR) bacteria. But now, the University of Southern California (USC) has developed and patented an experimental vaccine that has been shown to protect against so-called “superbugs,” such as methicillin-resistant Staphylococcus aureus (MRSA), an AMR bacteria that causes potentially deadly staph infections in hospitals and other healthcare settings.

The innovative approach focuses on bolstering the patient’s immune system itself, rather than relying on proteins to fight infections, according to a USC Today article. 

Developed by senior study author Brad Spellberg, MD, Chief Medical Officer at the Los Angeles General Medical Center, and colleagues, “The experimental vaccine takes an entirely different approach: It gooses the body’s preexisting supply of pathogen-gobbling immune cells called macrophages, which engulf and digest bacteria, fungi, and other bad actors. These activated fighters, found in all tissues, quickly neutralize incoming invaders which might otherwise multiply rapidly and overwhelm the body’s defenses,” USC Today reported. 

“This is very different from developing new antibiotics,” Jun Yan, a doctoral student at Keck School of Medicine and the study’s first author, told USC Today. “This is using our own immune system to fight against different superbugs, which is a different approach than everybody else.”

To develop the vaccine [the USC researchers] formed a biotechnology startup called ExBaq LLC in Bethesda, Md.

They published their findings in the journal Science Translational Medicine title, “A Protein-Free Vaccine Stimulates Innate Immunity and Protects against Nosocomial Pathogens.”

Ishwar K. Puri, PhD

“The pandemic stimulated unprecedented innovation in vaccine development, where federal funding and university-industry partnerships were game changers for translating promising discoveries from academic labs for the good of all,” said Ishwar K. Puri, PhD (above), senior vice president of research and innovation at USC. “We are both pleased and proud of the critical support the USC Stevens Center provided to enable the development of ExBaq’s experimental vaccine that protects vulnerable populations from serious infections.” Clinical laboratories that work with hospitals in the fight against hospital-acquired infections understand the importance of this discovery. (Photo copyright: University of Southern California.)

USC Vaccine Details

The USC team developed a “protein-free vaccine, composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan, that stimulates the innate immune system and confers protection,” the researchers wrote in Science Translational Medicine.

“Tested in two independent labs, the vaccine works within 24 hours and lasts for up to 28 days. In lab models, the number of pathogen-eating immune cells in the blood increased dramatically, and survival time of invasive blood and lung infections improved. Early data suggest that a second dose could extend the window to prevent infection,” USC Today reported.

Unlike anything currently available, the new vaccine focuses on boosting the body itself instead of creating antibodies against certain pathogens. A mere dose of the vaccine is described to “provide rapid protection against nine different bacteria and fungi species,” USC Today noted.

“It’s an early warning system. It’s like Homeland Security putting out a terror alert. Everybody, keep your eyes open. Keep an eye out for suspicious packages. You’re alerting the soldiers and tanks of your immune system. The vaccine activates them,” Spellberg told USC Today

“The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant healthcare-associated infections,” the researchers wrote in Science Translational Medicine.

Great Need for This Protection

According to the federal Centers for Disease Control and Prevention (CDC), 1.7 million infections and 99,000 deaths are caused by HAIs annually.

“Patients who acquire infections from surgery spend, on average, an additional 6.5 days in the hospital, are five times more likely to be readmitted after discharge and twice as likely to die. Moreover, surgical patients who develop infections are 60% more likely to require admission to a hospital’s intensive care unit. Surgical infections are believed to account for up to 10 billion dollars annually in healthcare expenditures,” the CDC reports.

“All hospitalized patients are susceptible to contracting a [hospital-acquired] infection. Some patients are at greater risk than others: young children, the elderly, and persons with compromised immune systems are more likely to get an infection. Other risk factors are long hospital stays, the use of indwelling catheters, failure of healthcare workers to wash their hands, and overuse of antibiotics,” the CDC notes.

Therefore, USC’s new vaccine may be just what the doctor ordered to protect patients in hospitals and other healthcare settings from deadly HAIs.

Looking Ahead

There are currently no vaccines that are FDA-approved that treat “the most serious antibiotic resistant infections,” USC Today reported.

“Even if there were such vaccines, multiple vaccines would have to be deployed simultaneously to protect against the full slate of antibiotic-resistant microbes that cause healthcare-acquired infections,” Brian Luna, PhD, assistant professor of molecular microbiology and immunology at USC’s Keck School of Medicine, told USC Today

Thus, USC’s new vaccine could be a boon to hospital antimicrobial stewardship programs. But so far, it has only been tested on mice.

“The next step is getting guidance from the US Food and Drug Administration (FDA) on the design of a clinical trial. The first such trial would be done in healthy volunteers to find the right dose of vaccine that is safe and triggers the same kind of immune response in people as seen in the mice,” USC Today reported.

ExBaq LLC has begun talking with potential larger partners who might be willing to help develop the vaccine into clinical testing.

For years hospitals and other healthcare settings—such as long-term care facilities, urgent care clinics, and clinical laboratories—have fought an uphill battle against superbugs. So, for a vaccine to be on the horizon that can prevent life-threatening hospital-acquired infections would be a game changer.

With antimicrobial stewardships being a requirement in all hospitals, medical laboratory managers and microbiologists may celebrate this new development and its potential to be a useful tool in fighting antimicrobial resistant bacteria in their facilities.

—Kristin Althea O’Connor

Related Information:

Superbugs Including MRSA Thwarted by Unconventional Vaccine

A Protein-Free Vaccine Stimulates Innate Immunity and Protects Against Nosocomial Pathogens

Superbug Vaccine “Hulkifies” Macrophages in Mouse Model

UCSF Researchers Identify Genetic Mutation That Promotes an Asymptomatic Response in Humans to COVID-19 Infection

Understanding why some people display no symptoms during a COVID-19 infection could lead to new precision medicine genetic tests medical labs could use to identify people with the mutated gene

New research from the University of California San Francisco (UCSF) may explain why some people could get COVID-19 but never test positive on a clinical laboratory test or develop symptoms despite exposure to the SARS-CoV-2 coronavirus.

According to the UCSF study, variations in a specific gene in a system of genes responsible for regulating the human immune system appears to be the factor in why about 10% of those who become infected with the virus are asymptomatic.

These scientific insights did not receive widespread news coverage but will be of interest to clinical laboratory managers and pathologists who oversee SARS-CoV-2 testing in their labs.

Jill Hollenbach, PhD

“Some people just don’t have symptoms at all,” Jill Hollenbach, PhD (above), Professor of Neurology at UCSF’s Weill Institute for Neurosciences and lead researcher in the study, told NBC News. “There’s something happening at a really fundamental level in the immune response that is helping those people to just completely wipe out this infection.” Identifying a genetic reason why some people are asymptomatic could lead to new precision medicine clinical laboratory diagnostics for COVID-19. (Photo copyright: Elena Zhukova /University of California San Francisco.)

Fortunate Gene Mutation

According to the Centers for Disease Control and Prevention’s (CDC) COVID Data Tracker, as of April 5, 2023, a total of 104,242,889 COVID-19 cases have been reported in the United States. However, according to a CDC Morbidity and Mortality Weekly Report (MMWR), “Traditional methods of disease surveillance do not capture all COVID-19 cases because some are asymptomatic, not diagnosed, or not reported; therefore, [knowing the true] proportion of the population with SARS-CoV-2 antibodies (i.e., seroprevalence) can improve understanding of population-level incidence of COVID-19.”

Jill Hollenbach, PhD, lead researcher in the UCSF study and Professor of Neurology at UCSF’s Weill Institute for Neurosciences, runs the Hollenbach Lab at UCSF. The lab specializes in the study of two important elements in human immune response:

She also participates in the COVID-19 HLA and Immunogenetics Consortium, a group of academic researchers, clinical laboratory directors, journal editors, and others who examine the role of HLA variations in determining COVID-19 risk.

Hollenbach’s research identified an HLA variant—known as HLA-B*15:01—that causes the human immune system to react quickly to SARS-CoV-2 and “basically nuke the infection before you even start to have symptoms,” she told NPR.

“It’s definitely luck,” she added. “But, you know, this [gene] mutation is quite common. We estimate that maybe one in 10 people have it. And in people who are asymptomatic, that rises to one in five.”

The researchers published their findings on the medRxiv preprint server titled, “A Common Allele of HLA Mediates Asymptomatic SARS-CoV-2 Infection.” The UCSF study has not yet been peer-reviewed.

UCSF Study Methodology

“HLA variants are among the strongest reported associations with viral infections,” the UCSF study notes. So, the researchers theorized that HLA variations play a role in asymptomatic SARS-CoV-2 infections as well.

To conduct their study, shortly after the SARS-CoV-2 outbreak in 2020, the researchers recruited approximately 30,000 volunteer bone marrow donors from the National Marrow Donor Program to respond to periodic questions via a smartphone app or website. Because HLA variations can determine appropriate matches between donors and recipients, the database includes information about their HLA types.

Each week, respondents were asked to report if they had been tested for SARS-CoV-2. Each day, they were asked to report whether they had symptoms associated with COVID-19. “We were pretty stringent in our definition of asymptomatic,” Hollenbach told NBC News. “[The respondents couldn’t] even have a scratchy throat.”

The researchers eventually identified a cohort of 1,428 people who had tested positive for SARS-CoV-2 between February 2020 and April 30, 2021, before vaccines were widely available. Among these individuals, 136 reported no symptoms for two weeks before or two weeks after a positive test.

“Overall, one in five individuals (20%) who remained asymptomatic after infection carried HLA-B*15:01, compared to 9% among patients reporting symptoms,” the researchers wrote in their medRxiv preprint. Study participants with two copies of the gene were more than eight times more likely to be asymptomatic.

The UCSF researchers also looked at four other HLA variants and found none to be “significantly associated” with lack of symptoms. They confirmed their findings by reproducing the HLA-B association in two additional independent cohorts, one from an earlier study in the UK and the other consisting of San Francisco-area residents.

Individuals in the latter group had either tested positive for SARS-CoV-2 or reported COVID symptoms, and their DNA was analyzed to determine their HLA types.

Pre-existing T-Cell Immunity May Reduce Severity of COVID-19 Infection

The UCSF researchers also attempted to determine how HLA-B*15:01 plays a role in knocking out SARS-CoV-2 infections. They noted previous research that indicated previous exposure to seasonal coronaviruses, such as common cold viruses, could limit the severity of COVID-19. The scientists hypothesized that pre-existing T-cell immunity in HLA-B carriers may be the key.

The COVID-19 HLA and Immunogenetics Consortium website describes how HLA and T-cells work together to ward off disease. HLA “proteins are found on the surface of all cells except red-blood cells.” They’re “like windows into the inner workings of a cell,” and T-cells use the molecules to determine the presence of foreign proteins that are likely signs of infection. “Activated T-cells can kill infected cells, or activate B-cells, which produce antibodies in response to an infection,” the website explains.  

Hollenbach’s research team analyzed T-cells from pre-pandemic individuals and observed that in more than half of HLA-B carriers, the T-cells were reactive to a SARS-CoV-2 peptide. The scientists corroborated the hypothesis by examining crystal structures of the HLA-B*15:01 molecule in the presence of coronavirus spike peptides from SARS-CoV-2 and two other human coronaviruses: OC43-CoV and HKU1-CoV.

“Altogether, our results strongly support the hypothesis that HLA-B*15:01 mediates asymptomatic COVID-19 disease via pre-existing T-cell immunity due to previous exposure to HKU1-CoV and OC43-CoV,” the researchers wrote.

Can Genes Prevent COVID-19 Infections?

Meanwhile, researchers at The Rockefeller University in New York City are attempting to go further and see if there are mutations that prevent people from getting infected in the first place. NPR reported that they were seeking participants for a study seeking to identify so-called “superdodger” genes.

“You fill out a questionnaire online about your exposures to SARS-CoV-2,” explained Jean-Laurent Casanova, MD, PhD, professor, senior attending physician, and head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University, who is leading the study.

Study participants identified as possibly having superdodger genes receive a kit designed to collect saliva samples, after which the researchers sequence the respondents’ genomes. “We hope that in a group of 2,000 to 4,000 people, some people will have genetic mutations that tell us why they’re resistant to infection,” Casanova told NPR.

All this genetic research is in very early stages. But results are promising and may lead to new precision medicine clinical laboratory tests for identifying people who are predisposed to having an asymptomatic response to COVID-19 infection. That in turn could help scientists learn how to moderate or even eliminate symptoms in those unfortunate people who suffer the typical symptoms of the disease.   

—Stephen Beale

Related Information:

A Common Allele of HLA Mediates Asymptomatic SARS-CoV-2 Infection

What People with ‘Super Immunity’ Can Teach Us about COVID and Other Viruses

So, You Haven’t Caught COVID Yet. Does That Mean You’re a Superdodger?

If You Haven’t Gotten COVID Yet, This Might Be Why

Trends in Number of COVID-19 Cases and Deaths in the US Reported to CDC, by State/Territory

UC San Francisco Researchers Discover Why Some People Are Asymptomatic When Infected with COVID-19

Seroprevalence of Infection-Induced SARS-CoV-2 Antibodies—United States, September 2021–February 2022

Genomic Study Reveals Role of Human Papillomavirus in Cervical Cancer and Identifies Novel Therapeutic Targets for the Disease

Findings may help physicians tailor cervical cancer therapies to specific gene mutations and improve the accuracy of diagnostic screening tests for this disease

New scientific knowledge about the role of human papillomavirus (HPV) in the growth of cervical cancer is creating excitement within the medical community. Among other things, these findings could encourage more widespread vaccination against HPV. That in turn would lead to reduced Pap smear testing by pathology laboratories over time.

For these reasons, cytopathologists and cytotechnologists will be particularly interested in the research findings that were published as a first-ever, international genomic study of cervical cancer, which was published online December 25, 2013, at Nature.com. Researchers discovered that the location where HPV integrates itself into the human genome, is where it causes amplified gene expression that promotes and elevates mutated gene activity that may cause cervical cancer to develop. (more…)

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