A cadre of revolutionary vaccination approaches was paraded before an assembly of scientists at the third annual Stanford Vaccine Symposium.
This year’s event, held Oct. 23 in the Stanford Health Care Assembly Hall, was spearheaded by Stanford Medicine’s Bali Pulendran, PhD, director of the Institute for Immunity, Transplantation and Infection. Some 263 participants registered to attend in person and 135 people registered to attend virtually, as a dozen speakers — half of them from Stanford, the rest from private companies and other research institutions — presented analyses of immunological responses to current vaccines, thoughts on improving those responses, and descriptions of novel vaccination designs.
Lloyd Minor, MD, the Carl and Elizabeth Naumann Dean of the School of Medicine and vice president for medical affairs at Stanford University, offered opening remarks via video.
“Today’s program will take you to the cutting edge of science,” Minor said. “In the last 50 years, the research and development of vaccines have prevented life-threatening diseases and infections in approximately 150 million children, according to a recent study. Few can claim to have had as profound an impact on global health as those who develop vaccines.”
What Minor promised, the speakers delivered.
Needle-free vaccines you rub on your skin
Michael Fischbach, PhD, professor of bioengineering, described almost fantasy-like findings from his lab.
“Surprises do happen in science, and this is one of them,” said Fischbach, the Liu (Liao) Family Professor.
“Every square centimeter of skin on every human on the planet is colonized by Staphylococcus epidermidis,” an apparently harmless bacterial species, he said. Yet, despite the formidable barrier called skin that separates them from our insides, Fischbach’s team learned, our immune system, puzzlingly, boasts a powerful arsenal of antibodies precisely targeting that species. Perhaps, Fischbach speculated, this makes it easier to mount a quick response should the bug breach the skin after a cut, scratch or scrape and get inside our bloodstream, in which case it would become very dangerous.
Fischbach and his colleagues were able to determine a specific feature of S. epidermidis the immune system detects, use advanced but now common lab techniques to substitute a toxic component of the tetanus bacterium for that feature, and prevent mice from succumbing to what should be a deadly dose of that toxic tetanus pathogen by preemptively rubbing a cream containing the modified S. epidermidis organism on their fur and letting it soak into their skin.
The immune system appears perfectly able to mount a powerful, sustained response to a chosen microbe — no injection needed. Fischbach suggested that it may be possible to design pathogen-specific vaccines that can be applied simply by rubbing a modified-bacteria-containing cream on the skin.
“We’re very interested in whether we could make vaccines this way,” he said. “This is something that you could apply to yourself. It could arrive in the mail, like in a ketchup packet.”
The workaround
Despite vaccination’s glittering success as an overall disease-defeating strategy, many an individual vaccine has met with failure or at best achieved mediocre results, noted Mark Davis, PhD, the Burt and Marion Avery Family Professor and a professor of microbiology and immunology.
The annual seasonal influenza vaccine is such a mediocrity — its efficacy is about 60% at best, depending in part on how good a strain/vaccine fit is achieved each year — for a couple of reasons. Every flu season is preceded by a flurry of scientific guesswork because the virus that causes flu is highly prone to mutations and appears each year in a variety of strains, including some not previously seen. So, vaccinologists can never be entirely sure which strains to prioritize for inclusion.
But beyond that, each of us has an immune system that tends to be substantially more apt to mount a response to just one, not all three, of the strains carried in the annual vaccine.
“It’s called strain specificity,” Davis said. “Your immune system might be great at fighting one of those strains, but you get infected by another one” and down you come with the flu.
Davis and his colleagues devised an ingenious way around that dilemma: They wove immunity-inducing fragments of each of the three strains into a supportive matrix. This forced the immune cells that ingest, process and display these fragments, kicking off our immune response, to gobble and process all three varieties rather than just the one from the preferred strain. This ensures a robust immune response to all three strains — and probably also to the bird-flu virus if that should become necessary, Davis said.
Predicting individuals’ vaccine response
Antibodies — the proteinaceous, customized suction cups that immune cells secrete to tie up and disable microbial pathogens — are immensely diverse at their “tips,” their bespoke pathogen-binding business ends. But their “stalks” at the opposite ends have personalities, too — they determine which immune cells a given antibody molecule will adhere to and, importantly, whether the effect of the adherence will exert on that immune cell will be pro- or anti-inflammatory.
A group led by Taia Wang, MD, PhD, an associate professor of infectious diseases and of microbiology and immunology, has shown that a good deal of these antibody-to-cell meetups’ pro- or anti-inflammatory fate (a predictor of our clinical response to the pathogen we’ve been vaccinated against) depends on the presence or absence of a single pair of specialized sugar molecules (not the kind we eat) on the antibody stalk.
“Two antibodies identical in protein sequence with or without these two sugars have completely opposite activities in terms of regulating the inflammatory response to a pathogen,” Wang said.
As we grow older, she said, our antibody stalks become increasingly likely to be adorned with the sugar-group configuration favoring inflammation and, in the case of some pathogens, this is associated with more-severe inflammatory consequences during infection. Wang’s team is looking at the possibility of intervening to change the composition of those antibody stalks to meaningfully improve older people’s ability to fight off microbes and stay healthy for longer.
The quest for a universal vaccine
Pulendran, a professor of pathology and of microbiology and immunology, presented preclinical data in mice for a single universal vaccine that stimulates broadly protective immunity against many different classes of viruses, bacteria and other respiratory threats such as allergens. This could play a role, he said, by programming the immune system to provide broad immunity against one or another general type of pathogen (say, viral versus bacterial) for a few weeks to months ahead of an advancing wave of infection by a novel and poorly characterized pathogen, or one for which a highly effective pathogen-specific vaccine or treatment has yet to emerge from the developmental pipeline.
Pulendran’s group is seeking ways to prime the innate immune system via vaccination to remain in a heightened state appropriate to fighting off a still-poorly characterized, but (for example) clearly viral pathogen.
Our ancient innate immune system, the key driver of inflammation, recognizes broad features signifying an infecting pathogen’s general type (viral, bacterial, fungal or parasitic), and shifts into the appropriate state to combat that type of microorganism, while paying scant attention to the exact species or strain that’s doing the invading.
The evolutionarily newer adaptive immune system’s philosophy might be: Don’t get mad, get even. This precision-oriented arm of the immune system takes a week or longer to single out highly distinctive features of the infectious pathogen in question and then attack anything bearing those features — but, ideally, nothing else.
Meanwhile, during that first post-infection week or so, it’s the innate immune system that must bear the burden of combatting the pathogen, albeit with some risk of collateral damage to healthy tissues.
“The innate immune system has a form of immunological memory,” said Pulendran, who is the Violetta L. Horton Professor II. “This immune memory, we believe, is an emergent property that arises from the interplay between innate and adaptive immune cells.”
Pulendran’s group is exploring ways of vaccinating people in advance of, say, a still-mysterious viral pandemic in a way so that feedback from the adaptive immune system, stimulated by the vaccine, primes the innate immune system to remain in a heightened state appropriate to fighting off all viruses and bacteria, however unfamiliar.
In his introductory talk, Minor praised Pulendran, who assumed the directorship of the Institute for Immunity, Transplantation and Infection when Davis stepped down in 2024 after a decade at the helm.
“In a little over a year as director, you’ve accelerated the group’s excellence, and you’re expanding its influence on public health and the treatment of infectious diseases here and around the world,” Minor told Pulendran.
Other Stanford presenters were Catherine Blish, MD, PhD, professor of infectious diseases and the George E. and Lucy Becker Professor in Medicine; and Scott Boyd, MD, PhD, professor of food allergy and immunology and of pathology. Speakers from other institutions were Sarah Gilbert (University of Oxford), Andrea Carfi (Moderna), Neil King (University of Washington), Michela Locci (University of Pennsylvania) and Donna Farber (Columbia University).
