A newly reported study by a Stanford Medicine-led team has provided what the researchers suggest is the strongest evidence yet that a vaccine can reduce the risk of dementia. Taking advantage of a particular public health policy in Wales that means eligibility for the shingles (herpes zoster) vaccine is based on an individual’s exact date of birth, the team analyzed the health records of older adults, discovering that those who received the live attenuated vaccine were 20% less likely to develop dementia over the next seven years than those who did not receive the vaccine.

The findings, published in Nature, support an emerging theory that viruses that affect the nervous system can increase the risk of dementia. In their paper (“A natural experiment on the effect of herpes zoster vaccination on dementia,”) research lead and senior author Pascal Geldsetzer, MD, PhD, assistant professor of medicine, and colleagues, concluded, “Our substantial effect sizes, combined with the relatively low cost of the zoster vaccine, imply that, if these findings are truly causal, the zoster vaccine will be both far more effective as well as cost-effective in preventing or delaying dementia than existing pharmaceutical interventions.”

Shingles, a viral infection that produces a painful rash, is caused by the same virus—varicella zoster virus (VZV)—that causes chicken pox. After people contract chicken pox, usually in childhood, the virus stays dormant in the nerve cells for life. In people who are older or have weakened immune systems, the dormant virus can reactivate and cause shingles.

Dementia affects more than 55 million people worldwide, with an estimated 10 million new cases every year. Decades of dementia research have largely focused on the accumulation of plaques and tangles in the brains of people with Alzheimer’s, the most common form of dementia. But a lack of breakthroughs in prevention or treatment is leading some researchers to explore other avenues, including the role of certain viral infections.

In their newly released Nature paper, Geldsetzer and colleagues pointed out, “Recently, evidence has grown that neurotropic herpesviruses may have a role in the pathogenesis of dementia. One approach to targeting herpesviruses is vaccination.” However the team continued, vaccines are increasingly being recognized as eliciting a broader immune response that can have important off-target effects. To date, they continued, “… studies in cohort and electronic health record data on the effect of vaccination receipt on dementia have simply compared the occurrence of dementia among those who received a given vaccination and those who did not.”

Such studies have to assume that characteristics that are different between vaccinated and unvaccinated individuals—and that are also related to dementia—have been sufficiently well measured and modeled so that there are no remaining factors that might confound any relationship between vaccination receipt and dementia. But, as the team commented, “This assumption of no confounding bias is often implausible because it has to be assumed that the study has detailed data on factors that are difficult to measure, such as personal motivation or health literacy.”

So, while previous studies based on health records have linked the shingles vaccine with lower dementia rates, they could not account for a major source of bias, in that people who are vaccinated also tend to be more health conscious in many difficult-to-measure ways. Behaviors such as diet and exercise, for example, are known to influence dementia rates, but are not included in health records.

“All these associational studies suffer from the basic problem that people who get vaccinated have different health behaviors than those who don’t,” said Geldsetzer. “In general, they’re seen as not being solid enough evidence to make any recommendations on.”

Two years ago Geldsetzer recognized a fortuitous “natural experiment” in the rollout of the shingles vaccine in Wales that offered a potential way to deal with this bias. “To provide causal as opposed to correlational evidence, we take advantage of the fact that, in Wales, eligibility for the zoster vaccine was determined on the basis of an individual’s exact date of birth,” the investigators explained. The vaccine being used at that time contained a live-attenuated, or weakened, form of the virus.

The vaccination program, which began Sept. 1, 2013, specified that anyone who was 79 on that date was eligible for the vaccine for one year. (People who were 78 would become eligible the next year for one year, and so on.) People who were 80 or older on Sept. 1, 2013, were out of luck—they would never become eligible for the vaccine. The authors summarized, “Those born before 2 September 1933 were ineligible and remained ineligible for life, whereas those born on or after 2 September 1933 were eligible for at least one year to receive the vaccine.”

These rules, designed to ration the limited supply of the vaccine, also meant that the slight difference in age between 79- and 80-year-olds made all the difference in who had access to the vaccine. By comparing people who turned 80 just before Sept. 1, 2013, with people who turned 80 just after, the researchers could isolate the effect of being eligible for the vaccine.

The circumstances, well-documented in the country’s health records, were about as close to a randomized controlled trial as you could get without conducting one, Geldsetzer pointed out. “Importantly, individuals who are only a few weeks apart in age are not expected to differ systematically from each other,” the authors commented. “That is, all potential confounding variables are in expectation balanced between our comparison groups.” By taking advantage of what they described as “this unique natural experiment” the scientists could avoid confounding “more credibly” than other studies that had compared vaccine recipients to non-recipients while trying to control for “the myriad of differences” between the groups.

For their reported study, Geldsetzer and colleagues looked at the health records of more than 280,000 older adults who were 71 to 88 years old and did not have dementia at the start of the vaccination program. They focused their analysis on those closest to either side of the eligibility threshold—comparing people who turned 80 in the week before the cutoff with those who turned 80 in the week after. “We know that if you take a thousand people at random born in one week and a thousand people at random born a week later, there shouldn’t be anything different about them on average,” Geldsetzer said. “They are similar to each other apart from this tiny difference in age.”

The same proportion of both groups likely would have wanted to get the vaccine, but only half, those almost 80, were allowed to by the eligibility rules. “What makes the study so powerful is that it’s essentially like a randomized trial with a control group—those a little bit too old to be eligible for the vaccine—and an intervention group—those just young enough to be eligible,” Geldsetzer added.

Over the next seven years, the researchers compared the health outcomes of people closest in age who were eligible and ineligible to receive the vaccine. By factoring in actual vaccination rates—about half of the population who were eligible received the vaccine, compared with almost none of the people who were ineligible—they could derive the effects of receiving the vaccine.

They found that, as expected, the vaccine reduced the occurrence over that seven-year period of shingles by about 37% for people who received the vaccine, similar to what had been found in clinical trials of the vaccine. (The live-attenuated vaccine’s effectiveness wanes over time.)

By 2020, one in eight older adults, who were by then 86 and 87 years of age, had been diagnosed with dementia. But those who received the shingles vaccine were 20% less likely to develop dementia than those who were unvaccinated. “Scaled to account for the fact that not all those who were eligible received the vaccine, we find that actually receiving the zoster vaccine reduced the probability of a new dementia diagnosis by 3.5 (95% CI = 0.6–7.1; P = 0.019) percentage points, corresponding to a relative reduction of 20.0%,” the team wrote. “It was a really striking finding,” Geldsetzer said. “This huge protective signal was there, any which way you looked at the data.”

The scientists searched high and low for other variables that might have influenced dementia risk but found the two groups to be indistinguishable in all characteristics. There was no difference in the level of education between the people who were eligible and ineligible, for example. Those who were eligible were not more likely to get other vaccinations or preventive treatments, nor were they less likely to be diagnosed with other common health conditions, such as diabetes, heart disease, and cancer. “… we have provided evidence from a series of analyses against any of the possible remaining sources of bias being a likely explanation of our findings,” the authors stated.

The only difference was the drop in dementia diagnoses. “Because of the unique way in which the vaccine was rolled out, bias in the analysis is much less likely than would usually be the case,” Geldsetzer said. The team further noted, “By taking advantage of the fact that the unique way in which the zoster vaccine was rolled out in Wales constitutes a natural experiment, and examining each possible remaining source of bias, our study provides evidence that is more likely to be causal in nature than the existing, exclusively associational, evidence on this topic.”

The team did still analyze the data in alternate ways—using different age ranges or looking only at deaths attributed to dementia, for example—but the link between vaccination and lower dementia rates remained. “The signal in our data was so strong, so clear and so persistent,” Geldsetzer said.

In a further finding, the study showed that protection against dementia was much more pronounced in women than in men. “We observed large differences in the effect of zoster vaccination on dementia between women and men, with women benefitting more than men,” the investigators wrote. This could be due to sex differences in immune response or in the way dementia develops, Geldsetzer suggested. Women on average have higher antibody responses to vaccination, for example, and shingles is more common in women than in men.

Whether the vaccine protects against dementia by revving up the immune system overall, by specifically reducing reactivations of the virus or by some other mechanism is still unknown. Also unknown is whether a newer version of the vaccine, which contains only certain proteins from the virus and is more effective at preventing shingles, may have a similar or even greater impact on dementia. “… because the newer recombinant subunit zoster vaccine (Shingrix) replaced the live-attenuated zoster vaccine (Zostavax) in the United Kingdom only in September 2023, which is after our follow-up period ended, our effect estimates apply to the live-attenuated zoster vaccine only,” the authors stated.

Geldsetzer hopes the new findings will inspire more funding for this line of research. “Other than investing into randomized trials, investments into basic science research on the potential role of VZV and the immune response to the zoster vaccine in the pathogenesis of dementia could provide critical mechanistic insights,” the authors further noted. “At least investing a subset of our resources into investigating these pathways could lead to breakthroughs in terms of treatment and prevention,” Geldsetzer added.

In the past two years, his team has replicated the Wales findings in health records from other countries, including England, Australia, New Zealand, and Canada, that had similar rollouts of the vaccine. “We just keep seeing this strong protective signal for dementia in dataset after dataset,” he said. Geldsetzer has set his sights on a large, randomized controlled trial, which would provide the strongest proof of cause and effect. Participants would be randomly assigned to receive the live-attenuated vaccine or a placebo shot. “It would be a very simple, pragmatic trial because we have a one-off intervention that we know is safe,” he noted.

Geldsetzer is seeking philanthropic funding for the trial as the live-attenuated vaccine is no longer manufactured by pharmaceutical companies. And such a trial might not take long to see results. A graph of the Wales data tracking the dementia rates of those who were eligible and ineligible for the vaccine shows the two curves began to separate in about a year and a half.

In a related News & Views, Anupam B. Jena, MD, PhD, at the Department of Health Care Policy at Harvard Medical School and the Department of Medicine, Massachusetts General Hospital, commented that while it’s not yet clear exactly how herpes zoster vaccination lowers the risk of dementia, the reported study has profound implications. “The vaccine could represent a cost-effective intervention that has public-health benefits strongly exceeding its intended purpose,” Jena stated. “Given the substantial economic and social burden of dementia, policymakers and healthcare providers might need to reassess the value of widespread herpes zoster vaccination, particularly in older adults.”

RNA editing therapy developer AIRNA has closed on an oversubscribed $155 million Series B financing it said will help it advance its lead program targeting Alpha-1 antitrypsin deficiency (AATD) into a Phase I/II trial this year.

The financing comes less than a year after AIRNA completed a $90 million Series A, of which $60 million was raised just last summer, and at a time when many other startups have struggled to raise venture capital. While president and CEO Kris Elverum said he can’t speak to the broader challenges of early-stage companies pursuing capital, he told GEN Edge that AIRNA’s success with investors reflected their alignment with the company’s three-prong approach to RNA drug development.

“The first is that RNA editing is clearly going to be a breakthrough modality that will deliver multiple medicines to help patients,” Elverum said. “We’re using multiple proven components from other [RNA] modalities—in particular siRNA—to enable optimal potency at lower doses with safe, infrequent, subcutaneous administration.”

The second, he continued, is AIRNA’s effort to develop a best-in-class AATD treatment that will deliver optimal potency at lower doses with safe, infrequent, subcutaneous administration. The third, Elverum added, is AIRNA’s commitment to building a top-tier pipeline.

“AIRNA stands alone in pursuing the introduction of healthy variants to address common diseases with RNA editing. And we’re really excited about the future for what we were going to be able to do across multiple different diseases to help people,” Elverum said.

AIR-001 is designed to restore functional alpha-1 antitrypsin (M-AAT) protein production by precisely repairing the SERPINA1 mutation (PiZ) to address the underlying cause of both lung and liver disease. According to AIRNA, AIR-001 offers potent and durable M-AAT production, convenient, subcutaneous dosing, and well-tolerated safety.

Growing field targets AATD

By focusing on AATD, AIRNA joins a growing field of drug developers targeting the genetic condition. Furthest along is Wave Life Sciences, whose AATD candidate WVE-006 succeeded last October in the first-ever clinical demonstration of RNA editing in humans by achieving positive proof-of-mechanism in an early-phase clinical trial.

Later this year, Wave expects to present additional data from its Phase Ib/IIa RestorAATion-2 trial (NCT06405633) assessing the effect of multiple doses and a higher dose level of WVE-006, on the production of healthy, wild-type, M-AAT protein, and potentially the effect of extended dose intervals. In March, Wave said multi-dosing of patients was ongoing in the trial’s 200 mg cohort, while a second single dose cohort of 400 mg has been launched.

Also pursuing an AATD therapy is Beam Therapeutics, which won FDA clearance for its investigational new drug (IND) application to expand into the United States its ongoing Phase I/II trial (NCT06389877) of BEAM-302, an in vivo liver-targeting lipid-nanoparticle (LNP) formulation of base editing reagents. BEAM-302 is designed to treat AATD by correcting the disease-causing PiZ mutation.

Earlier in March, Beam announced positive initial safety and efficacy data from the trial: a single infusion of BEAM-302 led to rapid, durable, and dose-dependent increases in total AAT across all three dosages studied (20 mg, 40 mg, and 60 mg), as well as new production of corrected protein (M-AAT) and decreases in mutant AAT (Z-AAT). At the high 60 mg dosage, total AAT at day 28 nearly tripled from 4.4 to 12.4 µM, above the 11 µM protective threshold. Beam said the data established clinical proof-of-concept for BEAM-302 as a potential treatment for AATD, as well as for in vivo base editing.

On March 18, Prime Medicine unveiled a preclinical prime editing program designed to treat AATD by using a universal liver lipid nanoparticle (LNP) to edit the PiZ mutation (also known as Pi*Z or E342K) in SERPINA1. Prime said LNP delivery of its Prime Editors showed up to 72% precise correction of the SERPINA1 gene in the hepatocytes of fully humanized mice, restoring over 95% of serum AAT to the corrected isoform, with healthy M-AAT protein in the serum at levels “well above” 20 µM.

A developer of CRISPR-based gene editing therapies, Intellia Therapeutics, ended development in January of its AATD candidate NTLA-3001 as part of a cost-cutting restructuring that included the planned elimination of 27% of its workforce during 2025. That would translate to approximately 110 jobs, based on the workforce total of 403 full-time employees as of February 14 disclosed by Intellia in its Form 10-K annual report.

Functional cure

“I think it’s more important to be best for patients than it is to be first in patients, and the unique opportunity that we have for patients with AATD is to bring them a functional cure that is a very potent repair of the mutation that’s causing their disease,” Elverum said.

“That repair allows for high levels of M-AAT protein to be produced, which is what’s really important for lung function, but to do so at low doses that can be safe and infrequently administered subcutaneously and allow patients to maintain control and freedom over their healthcare choices over the long term,” he added.

AIRNA’s AIR-001 leads a pipeline about which the company has not disclosed many details. Elverum said AIRNA’s therapeutic areas of interest include cardiometabolic disease, where its sole disclosed program entails introducing an as-yet undisclosed beneficial variant in vivo. It’s a similar mechanism to a program in AIRNA’s revealed pipeline for an undisclosed therapeutic area.

Elverum won’t say whether AIRNA’s focus on cardiometabolic disorders will include developing alternatives to glucagon-like peptide 1 (GLP-1) therapies. GLP-1s indicated for obesity and diabetes have grown into blockbuster drugs generating billions of dollars in sales for leading companies Novo Nordisk and Eli Lilly—but which have been linked in studies to side effects ranging from sagging facial skin (“Ozempic face”) to loss of muscle mass.

AIRNA develops therapies based on its RESTORE+™ RNA editing platform. RESTORE+ first targets a defined site in the RNA strand, activating changes to composition and functionality of a therapeutically relevant protein. The platform optimizes the chemistry, sequence, and delivery of oligos that precisely engage the RNA at the target site upon delivery into the cell, with the goal of enabling precise, efficient, and safe RNA editing.

Following target engagement, the oligo recruits endogenous adenosine deaminases acting on RNA (ADAR) to make an adenosine-to-inosine (A-to-I) edit at the target site that is read as guanosine (G). The A-to-I edit changes the code in the RNA, enabling the repair of pathogenic point mutations, or inducing therapeutically effective gain or loss-of-function mutations that precisely change protein activity.

Growth plan

With operations divided between its home base in Cambridge, MA, and Tübingen, Germany, where the company oversees a research hub, AIRNA foresees growth to its staff of over 50 people this year.

“Our growth is really going to be focused on that next stage of our development as we are bringing our medicines to patients. You can think about the medical function, the manufacturing function, and the like. That is going to be key for us as we move forward,” Elverum said.

The Series B round brings AIRNA to $245 million in total capital raised, and comes less than a year after AIRNA closed on $60 million in financing that was also oversubscribed—and brought the value of the company’s Series A to $90 million. AIRNA emerged from stealth in September 2023 with its first $30 million in initial financing from an investor syndicate led by ARCH Venture Partners.

Venrock Healthcare Capital Partners led the Series B financing, with Forbion Growth serving as co-leader. Participants in the Series B included RTW Investments, Nextech Invest, ARCH Venture Partners, Forbion Ventures, ND Capital, and other undisclosed new and existing investors.

In connection with the latest financing, Melissa McCracken, PhD, a partner at Nextech Invest, has been appointed to AIRNA’s board.

“AIRNA’s innovative approach to RNA editing has the distinctive potential to improve health across large populations by introducing healthy genetic variants for many conditions,” stated Dirk Kersten, managing partner at Forbion. “We are excited to support the expansion of AIRNA’s pipeline of life-changing medicines and the advancement AIR-001 into the clinic.”

An edible biofilm, obtained from agricultural and fishing waste and developed by researchers at the São Carlos Institute of Chemistry of the University of São Paulo (IQSC-USP) in Brazil, allows the shelf life of strawberries (Fragaria x ananassa Duch.) to be extended.

In laboratory tests, the researchers found that over 12 days of refrigerated storage, the fruit coated with the film lost 11% weight and took between 6 and 8 days to start becoming contaminated with fungi, compared to 4 days for fruit not covered with the material.

The results of the work, carried out in collaboration with researchers from EMBRAPA Instrumentation and the Federal University of São Carlos (UFSCar), are published in the journal Food Chemistry.

“By applying the coating, it was possible to double the shelf life of strawberries kept under refrigeration and delay the dehydration of the fruit, while preserving the taste, texture and volatile compounds that give the fruit its characteristic aroma,” Mirella Romanelli Vicente Bertolo, first author of the study and a postdoctoral researcher at EMBRAPA Instrumentation, says.

The work began during Bertolo’s doctoral studies at IQSC-USP under the supervision of Professor Stanislau Bogusz Junior. During their research, they developed a technique that allowed them to extract 84.2% more antioxidants—substances with preservative properties—from the peel of pomegranate (Punica granatum L.) using natural deep eutectic solvents (NADES).

“More than 40% of the pomegranate, depending on the variety, is made up of peel, which is wasted. Our idea was to use this waste to obtain extracts rich in phenolic compounds with antioxidant and antimicrobial activities,” says Bogusz.

With the success of developing the extraction method, the researchers decided to test the hypothesis of incorporating the antioxidants in pomegranate into coatings based on gelatin and chitosan—a polymer (natural polysaccharide) found in the skeletons of crustaceans such as shrimp—to develop a protective film for fruit.

“We chose to use chitosan extracted from squid glia [inner shells] through a process of deacetylation of the chitin found in this mollusk, because it doesn’t have the problem of allergenicity like that obtained from shrimp. And we combined this material with another polymer, in this case gelatin, to improve its mechanical properties,” explains Bogusz.

Highly perishable fruit

The strawberry was chosen as a model system to test the effectiveness of the biofilm because it is one of the items with the highest loss rates in Brazilian supermarkets due to its perishability and short shelf life of about less than seven days under refrigeration.

“The strawberry is a fruit that has very high respiratory activity and a very low pH [acidity]. It’s therefore very susceptible to microbial attack. It’s also very moist and the fruit is small. Based on this, we hypothesized that if the material we developed worked, it’d be effective on any other fruit,” says Bogusz.

To test this hypothesis, the researchers coated strawberries with the edible film by immersion and evaluated the effects of the material on the physicochemical, microbiological and volatile profile and sensory characteristics of the fruit over 12 days of refrigerated storage.

The results indicate that the material forms a film on the surface of the fruit that acts as a barrier to the passage of microorganisms, moisture loss and gas exchange, modifying the strawberry’s respiration. In this way, the coating slows down the metabolism of the fruit during the post-harvest period, thereby increasing its shelf life and preserving the color, firmness and bioactive compounds of the fruit.

“We found that the film made it possible to maintain the texture, delay contamination by microorganisms and reduce the loss of fruit mass, which is observed when the strawberry shrivels. This happens very often with uncoated fruit because it easily loses water and dehydrates,” says Bertolo.

According to the researcher, the film also made it possible to reduce the severity of fungal damage and improve the volatile profile of the fruit. “The material made it possible to preserve 40% more of the compounds responsible for the fruit’s aroma,” says Bertolo.

The biofilm also didn’t interfere with the sensory characteristics of the fruit, such as flavor, as confirmed by sensory analysis tests conducted with undergraduate chemistry students at IQSC-USP.

“The results of the tests showed that there were no differences in the taste, aroma or visual characteristics of strawberries coated with the material compared to strawberries without the film,” says Bertolo.

The researchers have filed a patent application for the formulation and intend to license the technology to interested companies.

Economic analyses indicate that the coating could cost an estimated BRL 0.15 per fruit.

“This is a cost that consumers may be willing to pay for fruit with a longer shelf life and greater usage,” Bertolo estimates.