Train passengers on the East Coast rail line, which runs between London and Aberdeen, are being warned part of the route is shut for the next nine days.
Network Rail says electrification work requires complete closure of the line west of Edinburgh from Saturday until 25 January.
Engineering work between Haymarket and Dalmeny is part of a £340m electrification project which Network Rail says is designed to deliver greener, more reliable services in future.
Some bridges are being rebuilt and raised, or tracks lowered to make room for overhead line installation.
ScotRail says thousands of passengers a day will be affected and they should check on services before travelling.
Some trains are being diverted through Stirling and Perth, whilst others are replaced by buses.
Mark Ilderton, ScotRail’s service delivery director, described the works as “significant”.
“Network Rail’s upcoming work is a vital stage in the Fife electrification project, paving the way for long-term improvements that will benefit customers for years to come,” he said.
“We’ve put alternative travel plans in place to help keep people moving, and we encourage customers to take a moment to check their options before travelling.
“Some journeys may take longer than usual, so planning ahead will make things easier.
“Our website and the ScotRail app have the latest information, and we’ll continue to provide clear updates and support throughout the works.”
“Today the Trump Administration announced a plan to build a more reliable and affordable electricity supply for Americans in the mid-Atlantic. We share the goal of ensuring affordable, reliable energy for American families and our economy, and we applaud the bipartisanship emerging to tackle America’s outdated grid challenges. Amazon is paying our full energy costs and is committed to ensuring our data centers don’t increase consumers’ electricity bills, and we’ve been clear that every major energy user should do the same. We’re working with grid operators, utilities, and other partners to ensure the grid is prepared to meet future demand and that costs are not passed on to ratepayers.”
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If you are wondering whether Parsons shares offer fair value right now, the key is to look past the headline price and focus on what the market is really pricing in.
The stock last closed at US$72.22, with returns of 5.9% over 7 days, 17.1% over 30 days, 16.1% year to date, and a 24.3% decline over 1 year. The 3 year and 5 year returns stand at 71.6% and 89.0% respectively.
These mixed returns give important context for any valuation work, as they hint that investor expectations and risk perceptions have shifted at different points over the last few years. Recent company news and sector developments, including contract activity and broader market sentiment toward government and infrastructure related services, help explain why the share price has not moved in a straight line.
Simply Wall St currently gives Parsons a valuation score of 3 out of 6 based on its checks for potential undervaluation. Next we will look at what that means across different valuation methods, before finishing with a simple framework that can often give an even clearer view of value.
Find out why Parsons’s -24.3% return over the last year is lagging behind its peers.
A Discounted Cash Flow, or DCF, model estimates what a business could be worth today by projecting its future cash flows and then discounting those cash flows back to a present value.
For Parsons, Simply Wall St uses a 2 Stage Free Cash Flow to Equity model based on cash flow projections. The latest twelve month free cash flow is about $388.6 million, and analysts plus modelled estimates project free cash flow reaching around $619.6 million in 2035, with interim projections such as $390.6 million in 2026 and $495 million in 2028. All of these figures are in US$ and are below $1b, so they remain in the hundreds of millions range.
When these projected cash flows are discounted back and combined, the model arrives at an estimated intrinsic value of about $101.65 per share. Compared with the recent share price of $72.22, this implies an intrinsic discount of roughly 29.0%, which indicates that Parsons is trading below this DCF estimate.
Result: UNDERVALUED
Our Discounted Cash Flow (DCF) analysis suggests Parsons is undervalued by 29.0%. Track this in your watchlist or portfolio, or discover 869 more undervalued stocks based on cash flows.
PSN Discounted Cash Flow as at Jan 2026
Head to the Valuation section of our Company Report for more details on how we arrive at this Fair Value for Parsons.
For a profitable company like Parsons, the P/E ratio is a useful way to gauge what investors are currently willing to pay for each dollar of earnings. It captures not only today’s profitability but also what the market expects for future earnings and the risks around those expectations.
In general, higher growth expectations and lower perceived risk can support a higher “normal” or “fair” P/E, while slower expected growth or higher risk tends to justify a lower multiple. Parsons currently trades on a P/E of 32.08x. That sits above the Professional Services industry average of 24.92x and below the peer group average of 43.99x. This shows the stock is priced somewhere between broader sector levels and its closest peers.
Simply Wall St’s Fair Ratio for Parsons is 26.01x. This is a proprietary estimate of what a reasonable P/E might be, given factors such as earnings growth, profit margins, industry, market cap and company specific risks. Because it blends these inputs, the Fair Ratio can often be more tailored than a simple comparison with peers or the industry alone. On this basis, Parsons’ current P/E of 32.08x sits above the Fair Ratio, which points to a richer valuation on this metric.
Result: OVERVALUED
NYSE:PSN P/E Ratio as at Jan 2026
P/E ratios tell one story, but what if the real opportunity lies elsewhere? Discover 1445 companies where insiders are betting big on explosive growth.
Earlier we mentioned that there is an even better way to understand valuation, so let us introduce you to Narratives, which are simply your story about Parsons, linked to your own forecast for revenue, earnings and margins, and then to a Fair Value that you can easily compare to the current share price.
On Simply Wall St’s Community page, Narratives let you input your assumptions, connect them to a financial model, and see a Fair Value that updates automatically when new information like earnings releases, contract announcements or guidance changes is added to the platform.
Because different investors can hold different views, one Parsons Narrative might lean closer to the consensus Fair Value of about US$84.64 per share using a 5.03% revenue growth rate, a 4.85% profit margin and a 30.29x future P/E. Another could assume more conservative or more optimistic numbers, giving you a clear, side by side sense of how your Parsons view compares with others and whether the current price looks high or low against your own Fair Value.
Do you think there’s more to the story for Parsons? Head over to our Community to see what others are saying!
NYSE:PSN 1-Year Stock Price Chart
This article by Simply Wall St is general in nature. We provide commentary based on historical data and analyst forecasts only using an unbiased methodology and our articles are not intended to be financial advice. It does not constitute a recommendation to buy or sell any stock, and does not take account of your objectives, or your financial situation. We aim to bring you long-term focused analysis driven by fundamental data. Note that our analysis may not factor in the latest price-sensitive company announcements or qualitative material. Simply Wall St has no position in any stocks mentioned.
Companies discussed in this article include PSN.
Have feedback on this article? Concerned about the content? Get in touch with us directly. Alternatively, email editorial-team@simplywallst.com
Combination therapy of botensilimab (BOT) plus balstilimab (BAL) was approved Monday as an updated national treatment protocol for patients with certain ovarian cancers and soft tissue sarcomas (STS) by France’s National Agency for Medicines and Health Products Safety (ANSM).1
BOT plus BAL was originally approved to treat microsatellite-stable (MSS) metastatic colorectal cancer without active liver metastases. The extension, now approved for STS, will help address unmet medical needs in the disease space and allow more patients with advanced solid tumors access to the dual therapy.
What Is Botensilimab Plus Balstilimab? Mechanism and Clinical Use
The inclusion of BOT plus Bal, a chemotherapy- and radiation-free immunotherapy, was based on findings from a phase 1b multicenter clinical trial (NCT03860272). While it is still being evaluated in clinical studies, it is available in a compassionate access setting authorized by ANSM. These settings refer to expanded access to investigational medical product treatments outside of clinical trials for patients with a serious or immediately life-threatening disease or condition.2 BOT is a human Fc-enhanced multifunctional anti-CTLA-4 antibody designed to boost both innate and adaptive anti-tumor immune responses. It augments immune responses across a wide variety of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells, and inducing long-term memory responses.1
BAL is a novel, fully human monoclonal immunoglobulin G4 designed to block programmed cell death protein 1 (PD-1) from interacting with its ligands PD-L1 and PD-L2. Numerous research studies observed antitumor activity in heavily pretreated patients with BOT plus BAL therapy. These results show promise for targeting tumors that have historically demonstrated limited responsiveness to standard immunotherapy treatments.
France Expands National Access to BOT–BAL Through Early Access and Global Partnerships
Under Frances’s Autorisation d’Accès Compassionnel (AAC) framework, BOT plus BAL therapy is fully reimbursed. The AAC pathways allow patients with serious or life-threatening diseases who lack appropriate therapeutic alternatives to access hospital-based treatments. Aside from advanced or metastatic STS, the AAC reimburses BOT plus BAL therapy for MSS metastatic colorectal cancer without active liver metastases and platinum-refractory or platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.
The implementation of a multi-tumor early access framework under one nationally standardized protocol represents an unusual level of national early access. However, this expansion of AAC reimbursement for colorectal cancer, ovarian cancer, and STS allows equitable access for patients to receive consistent hospital-based care for an investigational treatment.
In addition to expanding access across France, Agenus, a clinical-stage biotechnology company and biologic manufacturer of BOL plus BAL, recently announced its partnership with Zydus Lifesciences Ltd, an Indian pharmaceutical company, to accelerate global development.3
The $141 million collaboration has granted Zydus exclusive rights to develop and commercialize BOT plus BAL in India and Sri Lanka. The collaboration announced in June 2025 will include an upfront consideration of $75 million cash for transferring biologics manufacturing facilities; an equity investment purchased by Zydus of Agenus of $16 million; a contingent milestone payment of up to $50 million to Agenus for BOT plus Bal production orders; and an exclusive license by Zydus with the rights to develop, for which Agenus is eligible to receive a 5% royalty on net sales.
“With these foundations in place, our focus in 2026 is disciplined execution—advancing our Phase 3 program, broadening paid patient access through authorized pathways, and progressing toward regulatory submission,” Garo Armen, PhD, chairman and chief executive officer of Agenus, said in a press release.
References
1. France expands national AAC access for Agenus’ Botensilimab + Balstilimab for ovarian cancer and soft-tissue sarcomas. News release. BioSpace. January 12, 2026. Accessed January 15, 2026. https://www.biospace.com/press-releases/france-expands-national-aac-access-for-agenus-botensilimab-balstilimab-for-ovarian-cancer-and-soft-tissue-sarcomas
2. Expanded access. U.S. Food and Drug Administration. August 9, 2025. Accessed January 15, 2026. https://www.fda.gov/news-events/public-health-focus/expanded-access
3. Agenus announces closing of $141M strategic collaboration with Zydus Lifesciences to advance BOT+BAL and strengthen U.S. Manufacturing Readiness. Agenus. News release. January 15, 2026. Accessed January 15, 2026. https://investor.agenusbio.com/news/news-details/2026/Agenus-Announces-Closing-of-141M-Strategic-Collaboration-with-Zydus-Lifesciences-to-Advance-BOTBAL-and-Strengthen-U-S–Manufacturing-Readiness/default.aspx
Professor Geert Rouwenhorst recently spoke with Rob Young at BBC – Business Daily. In the episode “Bonds: Heroes or villains” he discussed Yale University’s 378 year-old Dutch bond, housed in the Beinecke Library. The 1648 document, issued by Hoogheemraadschap Lekdijk Bovendams, a water authority, incredibly, continues to collect interest every year.
Podcast transcript (04:58 – 09:01):
RY: That mention of the Netherlands is a great opportunity to talk about a piece of living bond history from there. Let me take you back to 1648. Picture this, a water company in the famously wet Netherlands needs cash to build a levee. It doesn’t raise taxes, it borrows money by issuing bonds. The IOU isn’t written on paper but on vellum, goat skin, almost four centuries old, and one of those original bonds survives and it’s still collecting interest. The bond holder is Yale University in the United States.
RY: Hi Geert. How are you doing?
GR: Very well, thank you.
RY: Geert Rouwenhorst, the Dutch Professor of Finance at Yale showed me his prized possession over a video link. It’s history you can hold in your hands and proof that bonds aren’t just about money. They contain stories that stretch across centuries.
GR: It’s a manuscript bond, which means it’s sort of written on vellum, actually, at that time and what’s unusual about this bond is that it still pays interest.
RY: Can you read what it says? The writing looks incredibly old.
GR: It is old and if you just look at it first it just looks like an old manuscript. Although I’m Dutch myself, it wouldn’t occur to me at a first look that this is actually a Dutch bond. The language itself was quite different from the way we sort of write and construct sentences today. So it is actually hard to read. When we acquired the bond, I actually contacted somebody with the knowledge of Medieval Dutch to kind of decipher what the bond was really about. It’s an obligation to pay interest over the equivalent of 1000 Carolus guilders which was the currency in the mid-seventeenth century in the Netherlands.
RY: And what was the original loan for? Why were these bonds issued?
GR: The organization that issued it is a water board or water authority. Their objective was to help defend the country against the water. If there weren’t any system of levees in the Netherlands half of it would be, you know, underwater and a big flood plain. So, these water authorities were these semi-governmental organizations that were set up to kind of organize people to join forces to combat the waters.
RY: And so you are still collecting interest on this almost 400 years after it was first issued, which is incredible, isn’t it given that presumably most bonds aren’t around for anything near that length of time.
GR: So there’s a number of reasons why it’s incredible and the first is that the instrument has survived. If we would have lost this bond, the physical document, there’d be nothing to present to collect the interest. So in some sense that’s a miracle. The second thing is that many of the perpetual bonds that were issued have call provisions which means that the issuer could at some point raise their hand and says, you know, enough already I’m going to just repay my obligations. Although they were issued to remain in perpetuity, I have the right to basically, you know, to repay these bonds early, but this one actually is not callable. That’s unusual about this.
RY: So your university then will continue to be entitled to annual interest payments forever.
GR: Forever. Now it’s not going to be, you know, a huge amount. As we said, it was 50 Carolus guilders. Carolus guilders don’t exist anymore. We collect the equivalent of about 11 euros and, uh I have it here in front of me. It’s eleven euros and thirty-five cents on this bond, about thirteen dollars. So every so many years we collect annual interest on this bond.
RY: I imagine the flight cost is considerably more than the interest payment you collected.
GR: I was actually visiting family so it kind of all worked out.
RY: And how long do you think you’ll be able to store it for before it disintegrates in some way.
GR: Vellum is incredibly sturdy. This could live for another thousand years, no problem.
Related articles: “Infinity has a price” Goetzmann, W., & Rouwenhorst, R. G. (2023, March/April). Infinity has a price: A 375-year-old Dutch bond that still pays interest to Yale. Yale Alumni Magazine.
NASA and DOE planning nuclear reactor on the moon in 4 years
A full moon is seen over the Lincoln Memorial and Arlington Memorial Bridge in Washington, DC.
A US reactor on the moon would provide continuous power to lunar bases and support future missions to Mars.
Credit:
Bill Ingalls/NASA
NASA and the US Department of Energy (DOE) announced an agreement on Jan. 13 to establish a nuclear reactor on the surface of the moon by 2030. The agencies plan to partner on research and development of a fission power system that would provide continuous power for lunar bases for years and support future missions to Mars.
The agreement follows an executive order signed by President Donald J. Trump in December to ensure US leadership in space by returning to the moon by 2028, establishing a permanent lunar outpost by 2030, and laying the foundation for Mars exploration.
“Achieving this future requires harnessing nuclear power,” said NASA administrator Jared Isaacman in a press release. Lunar-surface reactors could operate continuously for years without the need to refuel and without being affected by weather or sunlight conditions.
NASA and the DOE have a decades-long history of partnership developing power sources and propulsion technologies for space exploration. The agencies did not share any details on a budget for the project, choice of reactor technology, or how the reactor would be transported or built.
Russia and China, meanwhile, have also announced plans to collaborate on building a nuclear reactor on the lunar surface.
—Prachi Patel
EPA to reassess paraquat safety
A liquid is sprayed through a nozzle onto blades of grass.
The use of paraquat dichloride in the US has grown in recent years, particularly as some weeds have become resistant to glyphosate.
Credit:
Shutterstock
Lee Zeldin, the US Environmental Protection Agency (EPA) administrator, took to the social media platform X on Jan. 9 to announce that his agency will be reassessing the safety of paraquat dichloride.
“When new science raises questions, the Trump EPA will not look the other way,” Zeldin wrote. “EPA is requiring paraquat manufacturers to thoroughly prove that current uses are safe in real-world conditions.”
The EPA issued an interim registration-review decision for the pesticide, commonly called just paraquat, in 2021. In November, the agency released an updated review—based on a new study from the manufacturer Syngenta—finding that paraquat’s potential to evaporate from treated fields is more uncertain than previously thought.
The EPA is now requiring manufacturers to conduct new studies to show how much paraquat evaporates into the air, and the agency will update its analysis of how the pesticide affects people’s health through breathing exposure, according to a statement from press officer Jeffrey Landis. “The EPA will publish all their findings and if these new studies reveal additional risk, EPA is prepared to tighten protections, require tougher rules, or limit or revoke uses, including where that may be disruptive, because safety must come first,” he wrote.
Paraquat is sprayed on corn, cotton, soy, and other crops. Studies have linked exposure to the pesticide to Parkinson’s disease, although some scientists believe the evidence is inconclusive.
Syngenta says it “rejects the claims of a causal link between paraquat and Parkinson’s disease because it is not supported by scientific evidence,” citing a 2024 preliminary report (PDF) by California’s Department of Pesticide Regulation that determined that existing findings “do not demonstrate a direct causal association with exposure to paraquat and the increased risk of developing Parkinson’s disease.” The report did find, however, “a possible role for paraquat exposure when considered in tandem with other exposures or predisposing factors.”
Paraquat is currently banned in more than 70 countries, including Brazil, China, and the European Union.
—Delger Erdenesanaa
New Jersey bans PFAS in cosmetics, food packaging, and more
New Jersey is the latest state to enact legislation phasing out per- and polyfluoroalkyl substances (PFAS) from many consumer products. On Jan. 12, Governor Phil Murphy signed the Protecting Against Forever Chemicals Act, which requires manufacturers to stop adding PFAS to cosmetics, carpet and fabric treatments, and food packaging sold in the state by January 2028. The legislation also requires cookware manufacturers to label any products containing intentionally added PFAS by then.
A dozen other states already have laws restricting PFAS in food packaging, according to tracking by the Safer States alliance, and several also have laws restricting PFAS in carpets, fabric treatments, and personal care products.
“We know the damaging effect these substances have on the human body and our environment, so we are acting to remove them from consumer products that pose the greatest risk of direct exposure,” state senator Linda Greenstein, one of the sponsors of the bill, said in a statement on Monday.
The Protecting Against Forever Chemicals Act also appropriates an initial $5 million for the New Jersey Department of Environmental Protection to develop a program focused on reducing sources of PFAS contamination. The program will include research as well as ongoing monitoring and testing of PFAS in the air, water, soil, and wildlife.
—Delger Erdenesanaa
US strikes on Venezuela damage the country’s key research institute
Venezuelan minister for science and technology Gabriela Jiménez Ramírez said that the Venezuelan Institute of Scientific Research (IVIC) was struck by two US missiles during a Jan. 3 military operation to capture Venezuelan president Nicolás Maduro and first lady Cilia Flores.
In her statement, published on the social media site Telegram, Jiménez Ramírez said that five of the major research institute’s 24 centers were damaged in the attack: the centers of chemistry, ecology, mathematics, nuclear technology, and physics.
Of those, the mathematics center—which housed servers and other essential equipment—was “completely destroyed,” Jiménez Ramírez said. She did not specify how much damage the other four centers sustained.
Jiménez Ramírez condemned the attacks, calling them an “act of imperial aggression without precedent.” She added that there is no justification for attacking “a sanctuary of science,” which she says is vital for training professionals who will go on to help sustain the health and oil sovereignty of the country.
Following the capture of Maduro, US president Donald J. Trump discussed the US military operation in Venezuela in a press conference but did not mention the missiles that hit the IVIC. The US Department of Defense declined to comment on the situation.
Since the incident, the former vice president and current acting Venezuelan president Delcy Rodríguez has ordered that the reconstruction of the five IVIC centers begin immediately.
When this fall’s cohort of UNLV’s Rebels on Wall Street program stepped onto the trading floor of the New York Stock Exchange, the shift in the industry was immediately apparent.
The noise and chaos long associated with Wall Street— shouting traders, flashing paper tickets, and crowded floors — have largely disappeared. In their place are algorithms, data models, and screens executing transactions at speeds no human can match.
What students encountered was not the Wall Street seen in movies, but a quieter, faster, and far more technology-driven financial ecosystem where artificial intelligence and automation power decision-making.
That theme echoed throughout the week as students visited JPMorgan, Blackstone, Bank of America, Caption Partners, and Barclays. Across firms, professionals emphasized how deeply AI and data analytics are embedded in everything from trading and research to risk management and investment strategy. Students learned that in today’s financial landscape, technical and analytical fluency are foundational.
Three participants reflect on the experience and share their perspectives on how fintech is scripting the future of the industry:
Carlos Gomez Sanchez, who is earning dual undergraduate degrees in accounting and finance and is an active member of the Financial Management Association.
Nicole Castillo, who is pursuing her undergraduate degree in finance with a minor in accounting and participates in the Financial Management Association.
Josemaria Ladao, who is completing dual undergraduate degrees in finance and economics and is also an active member of the Financial Management Association.
UNLV Rebels on Wall Street participants tour the New York Stock Exchange trading floor, gaining insight into how technology and AI power today’s modern markets. (Daniel Chi/UNLV)
A New Wall Street Comes Into Focus
While students had studied AI and data-driven finance in the classroom, seeing its dominance in practice made the shift feel real in a new way.
For Sanchez, looking out over the NYSE floor was a defining moment.
“Seeing how much space was taken up by computers instead of jam-packed traders really showed how much the industry has evolved,” he said. “It was one thing to learn about it in class but another to see it happening at that scale.”
Others were surprised by how calm and controlled the trading environment felt even during major events like IPOs (initial public offering), when companies first offer shares to the public. Castillo expected far more noise, urgency, and chaos.
“I thought it would be hectic,” she said. “Instead, it was surprisingly quiet. Technology is doing a lot of the work now.”
Fintech & AI: Not Just Tools for the Future
Across firms, students learned that AI is already deeply embedded in daily operations. Tools scan real-time market data, analyze earnings calls, track news and social sentiment, support risk modeling, and assist with decision-making. Tasks that once took junior analysts hours to do manually can now be completed in minutes.
Castillo noted how advanced these systems have become: “AI tools can process information from so many sources all at once. It can scan news, earnings calls, and even market sentiment and turn it into insights in real time,” she said.
While none of this technology was entirely new to students, seeing how universally it was expected in professional settings reinforced the importance of mastering these tools before entering the workforce. Employers were clear that graduates are no longer simply asked whether they have exposure to data analytics and AI, but how fluent they can use them.
As the week went on, students began rethinking the skills they want to strengthen, especially in areas that employers repeatedly emphasized as critical, such as financial modeling, derivatives, and data-driven analytics.
UNLV students met with professionals at Barclays to learn how data and AI inform decision making in global finance. (Daniel Chi/UNLV)
When Classroom Concepts Come to Life
At Caption Partners, a firm specializing in derivatives, students recognized familiar concepts from their coursework. Derivatives — financial tools that get their value from other assets, like stocks, interest rates, or commodities— were no longer abstract equations, but tools actively used to manage risk and execute strategy.
Ladao said seeing theory applied in practice reinforced the value of his coursework. “Having learned derivatives this semester, seeing how they’re actually used in a firm’s business model felt like a full-circle moment,” he said.
It also demonstrates the relevance of UNLV’s emphasis on analytics, modeling, and emerging technologies. Students also noted that mentorship through the Financial Management Association helped them engage more confidently with industry professionals.
Sanchez said preparation before the trip made a tangible difference.
“Mentorship gave me the knowledge to ask better questions and contribute meaningfully during firm meetings.”
What the Future of Finance Looks Like
From student reflections, three themes emerged about the future of the field:
AI fluency is essential: Understanding how AI tools work, and where human judgment remains critical, is now a baseline expectation.
Human skills matter more, not less: As Castillo noted, interpersonal skills, collaboration, and emotional intelligence are becoming key differentiators in an increasingly automated field.
The pace of change is accelerating: Sanchez summarized this urgency succinctly: “The future of finance is moving faster than ever. You have to keep learning at the same pace.”
Students participate in a roundtable discussion in New York City focused on emerging trends shaping the future of finance. (Daniel Chi/UNLV)
Ready to Show Off Your Investment Skills?
Students who want to build these same strengths — teamwork, analytical thinking, and real-world investment experience — are encouraged to sign up for the 2026 President’s Investment Challenge. Open to students from all backgrounds.
Being able to quickly and efficiently diagnose COVID-19 is essential in monitoring the pandemic. Because the sampling process for saliva is noninvasive, and because it is inexpensive and minimizes the risk for transmissions to health care workers (Baghizadeh Fini, 2020), saliva sampling has excellent potential and advantages over other sampling methods from biological specimens such as the lower and upper respiratory tract (Wyllie et al., 2020; To et al., 2020). Given the significant individual heterogeneity in the saliva viral shedding (Ke et al., 2022; Hay et al., 2022), identifying biomarker(s) for viral shedding patterns will be crucial for improving public health interventions in the era of living with COVID-19.
To improve our understanding of SARS-CoV-2 infection dynamics in saliva to enable application of saliva testing in the fight against COVID-19, we quantified and stratified longitudinal virus dynamics in saliva samples from 144 mildly symptomatic individuals from the cohorts of the NFV clinical trial (Hosogaya et al., 2021) and the University of Illinois at Urbana-Champaign (Ke et al., 2022), and we uniquely analyzed the relationships among viral dynamics, clinical data, and micro-RNAs. Our mathematical modeling analysis indicates that viral dynamics in saliva may exhibit distinct patterns compared to those in the upper respiratory tract. We estimated that viral replication in saliva is characterized by a relatively rapid early growth phase, with a mean (standard deviation) doubling time of 1.44 (0.49) hours. Compared with prior studies analyzing viral dynamics in the upper respiratory tract using similar models, which reported doubling times of 2–4 hr (Ke et al., 2022; Gunawardana et al., 2022; Iyaniwura et al., 2024), our findings suggest that viral replication in saliva proceeds faster than in the upper respiratory tract. Multiple previous studies have also shown that viral loads in saliva rise more rapidly than in the nasal cavity, are detected with higher sensitivity early in infection, and reach their peak earlier (Ke et al., 2022; Migueres et al., 2022; Puhach et al., 2023; Savela et al., 2022; Smith et al., 2021).
In addition to the large heterogeneity in virus infection dynamics, we identified three groups (i.e. G1, G2, and G3) with different viral shedding patterns (Figure 2D). Immunocompromised patients have been reported to have a prolonged duration of viral RNA detection, lasting over three months, underscoring the critical role of host immune responses in controlling viral infections (Leung et al., 2022; Niyonkuru et al., 2021; Nakajima et al., 2021; Wei et al., 2021). Although oral immune responses remain poorly understood, Huang et al. recently confirmed by using single-cell RNA sequencing of the human minor salivary glands and gingiva that SARS-CoV-2 infection can trigger sustained, localized immune responses in saliva (Huang et al., 2021). In this study, we observed significant differences in the down-slopes of viral shedding in saliva among participants in different groups, with a more rapid decline in G1. This decline is likely attributed to a stronger immune response to SARS-CoV-2 in G1 participants than in participants in G2 and G3, as reflected in the death rate of infected cells due to the immune response (Figure 2D). Lower levels of viral replication have also been observed among infected participants with high baseline levels of mucosal IgA (but not IgG), as reported elsewhere (Havervall et al., 2022). Recently, we demonstrated that rapid anti-spike secretory IgA antibody responses can contribute to reducing duration of viral RNA detection and amounts in nasopharyngeal mucosa (Miyamoto et al., 2023). These findings highlight the importance of biomarkers that directly reflect an individual’s immune response, such as virus-specific antibody induction and T cell levels etc., in predicting viral shedding patterns. Therefore, quantifying the time-series pattern of mucosal IgA and its correlation with saliva viral load may provide crucial insights into the stratification of SARS-CoV-2 infection dynamics.
For the purpose of predicting viral shedding patterns during the early stage of infection, we first explored the association of 39 basic clinical variables, 8 daily symptoms, and the levels of 92 micro-RNAs with the stratified groups. However, none of the factors were significant (Table 1, Figure 3A, Figure 4B, Supplementary file 1A and Supplementary file 1F). On the other hand, it is noteworthy that all infection cases were mild and that most participants had clinical indicators within normal ranges. This lack of clinical heterogeneity within the cohort may have limited the ability to fully capture the diversity of infection dynamics. Moreover, the clinical parameters analyzed in this study are, a priori, unlikely to exhibit strong correlations with virologic outcomes. In contrast, we showed that mir-1846, which is an exogenous micro-RNA that is specifically classified as an Oryza sativa micro-RNA (osa-microRNA; Rakhmetullina et al., 2020), may exhibit a weak negative correlation. Exogenous micro-RNAs enter the human body primarily through food and can affect human metabolism by interacting and binding with human genes. mir-1846 is reported to interact with two human genes (Rakhmetullina et al., 2020) that are known to be associated with the progression of melanoma, various cancers, and leukemia. This suggests that mir-1846 levels may be linked to human immunity. Few studies have investigated the role of mir-1846 in humans, but our findings suggest the need for further investigations into the impact of this micro-RNA level on human immunity. Our research sheds light on the intricate patterns of viral shedding in saliva.
Our approach has several limitations that must be considered in our next study: First, our analysis was limited to participants with symptomatic infection and excluded those with asymptomatic infection (22 asymptomatic individuals out of a total of 182 individuals, i.e. 12% of participants) because we integrated datasets with different time scales from different cohorts. Although our data do not include participants infected with omicron variants, others have reported that the omicron variant may cause a higher proportion of asymptomatic infection (Garrett et al., 2022). Thus, evaluating the effect of asymptomatic infection will be important to update our stratification, especially for recent (or future emerging) VOCs. Second, potential viral rebound was neither prespecified nor systematically assessed. A subset of participants exhibited patterns consistent with possible rebound (e.g. S01-16 and S01-43 in Figure 2—figure supplement 1), which could affect estimates of viral RNA detection duration. Future studies should predefine an operational criterion for viral rebound and explicitly incorporate it into the modeling framework to strengthen robustness. Since both models considered in the present study cannot account for viral rebound, a more complex model would be required to capture this phenomenon. Third, micro-RNAs participate in the post-transcriptional regulation of gene expression; however, they do not provide direct insights into immune cell dynamics. Given the reported association between the duration of viral RNA detection and mucosal immunity as discussed above, it appears imperative to analyze modalities that are directly linked to the immune response in the future. Fourth, some of our results may have limited relevance to the current COVID-19 situation, as most people have now either been infected or vaccinated. Nevertheless, investigating the relationship between viral shedding patterns in saliva and various clinical and microRNA data, and developing a method to do so, remains important. Such research can offer valuable insights into the early response to emerging infectious viruses in the future.
Another potential limitation of this study is the timing of saliva specimen sampling, although we took great care to select and compare specimens from G1, G2, and G3 without bias. As a result of our clinical trial design (jRCT2071200023 Hosogaya et al., 2021; Miyazaki et al., 2023), participants were enrolled after the onset of symptoms, thereby restricting saliva specimen collection exclusively to the post-symptom phase. Unfortunately, we lack samples from the pre-infection, pre-symptomatic, and early infection phases. Consequently, the absence of individual-level baseline values for micro-RNA means that inter-participant heterogeneity in micro-RNA levels may obscure signals related to distinct viral infection dynamics in saliva.
In conclusion, our study revealed that the dynamics of SARS-CoV-2 infection in saliva can be classified into three groups based mainly on the duration of viral RNA detection. However, accurately predicting the variability in viral dynamics remains a challenging task, because it requires a more comprehensive understanding of the complex shedding patterns in saliva, as well as detailed clinical and molecular data. The identification of a sensitive, simple, and rapid biomarker for saliva viral shedding will be imperative for future COVID-19 outbreak control.
