Prologue

In August 2026, GSK announced the success of the Phase III clinical trial of its antisense oligonucleotide drug Bepirovirsen, achieving functional cure rates of 19%–26% in chronic hepatitis B, and Japan's Ministry of Health, Labour and Welfare has formally approved it for market launch. This is one of the most milestone-worthy breakthroughs in the history of global hepatitis B drug development.

When the news reached Beijing, Dong Xiaoyan was handling daily affairs in the office of Genecradle Therapeutics. Sixteen years earlier, he was still a PhD student who had spent six years at Fudan University worrying about graduation — running a startup while studying, stretched thin, and on the verge of giving up his dissertation defense. He could hardly have imagined that the "one-third" in his doctoral dissertation — a paper published in the Chinese journal Acta Virologica Sinica that colleagues felt was "a waste" — would, sixteen years later, become a cornerstone of the global hepatitis B drug and therapeutic vaccine R&D chain.

This is not only Dong Xiaoyan's story, but also a true narrative of how Chinese applied research — whether by accident or by necessity — has changed a global industry.

Chapter One: From Physician to Entrepreneur (1988–2005)

Dong Xiaoyan's story does not begin in the mold of the academic elite "prodigy."

In 1988, he graduated with a bachelor's degree from the First Military Medical University and entered clinical practice as a physician specializing in cardiovascular and cerebrovascular diseases. In those years he worked directly with patients, and came to understand medicine firsthand — a safe and effective drug can change a person's destiny.

But what clinical work alone could accomplish was extremely limited. Confronted with rare diseases (then referred to as "difficult and complicated cases" or syndromes), he began to wonder: rather than waiting for others to develop and manufacture good drugs, why not do it himself? In 1995, he left clinical practice to pursue a master's degree in the more fundamental field of immunology, while nurturing what was then a rather bold idea — developing new drugs and bringing them to industrialization. This idea was not accepted by mainstream opinion at the time; a clinician crossing over into gene therapy industrialization sounded like fantasy.

After entering the laboratory for graduate studies, he chose the research and application of adeno-associated virus (AAV) vectors. AAV vectors were then regarded as a technically demanding viral vector with great potential for gene therapy applications — safe, liver-tropic, and capable of long-term stable expression of transgenes. Hepatitis B, as it happened, is a liver disease.

In 2004, Dong entered the Institute of Genetics at Fudan University to pursue his PhD under Professor Xue Jinglun. The following year, he founded his second startup, Beijing FivePlus Molecular Medicine Research Institute Co., Ltd. (The company name "FivePlus" derives from "5+" on a five-point grading scale — a pursuit of excellence; he hoped his company could do some "foundation-laying" work for the gene therapy industry.) From then on, he began a painful yet joyful six-and-a-half-year life of "running a startup while pursuing a PhD."

Chapter Two: A "Failed" Plasmid and a "Give It a Try" Idea (2006–2009)

Another thread of the story began in Taiwan.

In 2006, the team of Huang L.R. at National Taiwan University published a groundbreaking paper in PNAS. Using hydrodynamic injection, they delivered an AAV-backbone plasmid carrying 1.2 copies of the HBV genome into the tail vein of mice, successfully establishing chronic HBV infection lasting more than six months in approximately 40% of C57BL/6 mice.

This paper inspired hepatitis B researchers worldwide, including the team of Professor Zhou Yusen at the Academy of Military Medical Sciences. Zhou decided to follow up on this approach — if the model could be optimized to be more stable and easier to operate, it would be of tremendous help to hepatitis B drug development.

They received support from Dr. Wu Xiaobing of the State Key Laboratory at the Institute of Virology, who provided the pAAV2-neo plasmid, used to construct the AAV-backbone plasmid pAAV2-neo/1.3HBV carrying 1.3 copies of the HBV genome. This was then injected into mice by the same hydrodynamic approach. But the results were disappointing: all mice showed only transient HBVemia and turned negative within ten days.

Why did it fail? The failure to reproduce Huang's experimental results could have been influenced by subtle differences in plasmid dose, mouse strain, and injection technique. Looking back now, the most fundamental reason is that hydrodynamic injection is itself a form of "brute-force" delivery — the transient hypertension it causes in the circulatory system triggers severe liver injury and immune responses, causing the introduced HBV genes to be cleared by the immune system within just a few days.

Zhou's team summarized this attempt in a Chinese-language paper, and the research work was considered concluded.

Yet this experiment, judged "unsuccessful," was noticed by someone else.

Dr. Wu Xiaobing was at the time a principal investigator at the State Key Laboratory of Viral Genetic Engineering, Institute of Virology, Chinese Academy of Preventive Medicine (headed by Academician Hou Yunde). She had her own judgment of the result — perhaps the problem lay not with the plasmid itself, but with the delivery method. An idea occurred to her: what if, instead of hydrodynamic injection, the plasmid were packaged into AAV virus and delivered through the virus's natural infection route?

The core technical expertise of FivePlus, the company founded by Dong, was precisely the packaging and production of AAV viruses. She suggested that Dong try this idea.

Wu then obtained the "failed" pAAV2-neo/1.3HBV plasmid from Zhou's team. The AAV vector backbone pAAV2-neo used to construct this plasmid was itself a technical achievement of Wu's team. This meant Dong knew the backbone structure of this plasmid inside out, and packaging it into AAV virus posed almost no technical obstacle for him.

He took the plasmid in hand, looked at it, and then made a decision that did not seem like a big one at the time but later proved crucial:

"Give it a try."

Chapter Three: The Preliminary Experiment with Three Mice (2009–2010)

When Dong received this plasmid, he faced a research direction that appeared to be already "dead": hydrodynamic injection of the AAV-backbone plasmid had been tried, and it had failed. But Dong held something no one else had — the AAV vector systems and AAV virus packaging technology accumulated by FivePlus.

He did not repeat the hydrodynamic injection. Instead, he took a fundamentally different route:

• Packaging this "failed" pAAV2-neo/1.3HBV plasmid into a liver-tropic recombinant AAV8 virus
• Injecting it, via ordinary tail-vein injection (non-high-pressure), into three C57BL/6 mice

This was merely an exploratory preliminary experiment — three mice, just to see what would happen.

Month 1: all three tested HBsAg-positive; month 2: still positive; month 3: still positive! He immediately scaled up and repeated the experiment, and the results were consistent.

This was a "wow" moment. The pAAV2-neo/1.3HBV plasmid, once deemed a dead end, achieved stable, reproducible chronic infection after being packaged into AAV8 virus — without any immunosuppression whatsoever.

Why did hydrodynamic injection (plasmid) fail, while AAV virus (tail-vein injection) succeeded?

Dong later analyzed this turning point himself: "AAV8 virus is itself a naturally liver-tropic infectious particle. It 'disguises' the HBV genome as a routine viral delivery, rather than 'activating' the immune system with high-pressure injection of plasmid DNA. The single-stranded DNA carried by AAV8 enters hepatocytes and then programmatically and stably converts into double-stranded DNA, which is transcribed into HBV antigens and replication intermediates. This 'gentle' delivery method happens to avoid the immune system's rapid clearance of the various HBV antigen proteins."

From the plasmid backbone pAAV2-neo, to AAV virus packaging, to animal model validation — all the technical modules came from the same collaborative network; the only missing piece was the idea of "stringing the three together." Wu provided the idea; Dong provided the execution.

Scientific and technological breakthroughs are sometimes just such a simple combination of "idea + technology" — but the premise is that the idea and the technology happen to be held within the same circle.

Chapter Four: A "Disdained" Paper and a "Make-Do" PhD Defense (2010–2011)

In November 2010, the teams of Dong and Wu published this study in the Chinese journal Acta Virologica Sinica. The paper's title was plain — "Establishment of a Mouse Model of Persistent Hepatitis B Virus Infection by In Vivo Transduction with Highly Liver-Tropic Recombinant AAV8." Dong was the first author, with Yuchi Jie, Wang Gang, and others as co-authors, and Tan Wenjie and Wu as co-corresponding authors.

After publication, Dr. Zhang Liguo of the Institute of Biophysics, Chinese Academy of Sciences, approached Dong with a serious proposal: withdraw the paper and resubmit it to Hepatology. This proposal was not unreasonable at the time: a paper on a disease animal model that solved a core pain point in hepatitis B research could well have earned a place in a top international journal. But Dong faced a very practical problem — he was anxious about completing his PhD, and withdrawing and resubmitting would mean a wait of at least six months to a year.

By the end of 2010, he had already spent six years in the program since enrolling in 2004. Although Fudan University was relatively lenient — PhD students could take up to eight years before defending — and Professor Xue had reassured him not to worry about a delayed defense, endless postponement was not a sustainable situation.

His doctoral dissertation consisted of three parts:

Of the three papers comprising his dissertation, two appeared in leading domestic Chinese journals and one in PLOS ONE. Judged by the "SCI-only" evaluation standards of the time, this publication record was hardly stellar — more importantly, he had never published a complete first-author research paper on core AAV vector construction methods, a gap that was an obvious weakness under the academic evaluation system of the day. But he no longer had time to keep struggling.

Moreover, Academician Hou Yunde, director of the State Key Laboratory of Viral Genetic Engineering, consistently encouraged the team to publish innovative work in domestic journals. Hou himself was a staunch supporter of domestic academic journals. Dong shared this philosophy, and when discussing the matter later, he said:

"Publishing good work in Acta Virologica Sinica is the same as publishing it in the Journal of Virology."

So he chose not to withdraw. The paper stayed in Acta Virologica Sinica — the impact was indeed different; had it been published in Hepatology, its international dissemination would have been much faster. But Dong made a pragmatic choice: graduate first.

In 2011, he finally completed his PhD defense. The dissertation "pieced together" from three parts was named an outstanding doctoral dissertation of the year, earning him his PhD from Fudan University. He then returned to his gene therapy industrialization work.

(Note: "High-Throughput Functional MicroRNAs Profiling by Recombinant AAV-Based MicroRNA Sensor Arrays," published in PLOS ONE in 2012, is an extended application of the methodology from Part 1 (the "AAV reverse infection array"). Dong is one of the authors, but it is not part of his doctoral dissertation.)

Chapter Five: The Seed Sprouts (2010–2015)

In the first few years after publication of the AAV-HBV model, it did not immediately cause a sensation. Dong and his team continued a series of optimization efforts to make it more user-friendly:

• 2012: Wang Gang, Dong Xiaoyan, Wu Xiaobing, et al. compared modeling differences between C57BL/6 and BALB/c mouse strains in Acta Virologica Sinica, finding that C57BL/6 mice have more stable immune tolerance and are better suited to simulating chronic infection.
• 2013: Wang Guojing, Dong Xiaoyan, Wu Xiaobing, et al. successfully used the model in the Chinese Journal of Biotechnology to evaluate the in vivo antiviral efficacy of entecavir (ETV) and lamivudine (LAM) — demonstrating that it could not only build models but also screen drugs.
• 2015: Zhu Xinyao, Dong Xiaoyan, Wu Xiaobing, et al. compared modeling efficiency across five serotypes (AAV1, 2, 5, 8, and 9) in the Chinese Journal of Biotechnology, confirming that AAV8 and AAV9 performed best and giving researchers more choices.

In that same year, 2010, Beijing FivePlus Molecular Medicine Research Institute Co., Ltd. and the National Institute for Viral Disease Control and Prevention of the Chinese Center for Disease Control and Prevention jointly filed a patent — meaning that from the outset they treated this model as a tool with commercial potential worth protecting.

But what truly took this model global was a key decision by FivePlus: to turn the rAAV8-1.3HBV virus into a standardized commercial product.

FivePlus's product manual specified two HBV subtypes (adr and ayw), multiple packaging specifications, and detailed quality-control standards (SDS-PAGE purity ≥85%, dot-blot hybridization titer testing, and Q-PCR testing added from 2018). The manual also carried explicit reminders: "For research use only," "must be handled in a BSL-2 laboratory," and "operators should be vaccinated against hepatitis B." A standardized commercial product manual meant the model had evolved from a laboratory "homemade method" into a standard tool replicable by any laboratory or pharmaceutical company worldwide.

Chapter Six: Seen by the World (2016–2020)

As FivePlus's products entered the market, the AAV-HBV model began appearing in the HBV animal models used by major global pharmaceutical companies developing hepatitis B drugs.

The 22 references listed in FivePlus's product manual sketch out a global map of applications:

• The Dion team in France (2013) used the model to establish HBV infection in HLA-expressing mice.
• The Li team in the United States (2016) used it to study the HBV receptor NTCP.
• GSK scientists (2018) used it to evaluate the in vivo antiviral effects of locked nucleic acid (LNA) oligonucleotides.
• The Liu Yan team at the 302 Hospital (2016) used it to build a model of the C genotype, the prevalent strain in China.
• The Hou Jinlin team at Southern Hospital (2018) used it to study the effects of IL-21 on the reactivation of HBV-specific CD8+ T cells.

Beyond these teams, nearly 100 companies — including Johnson & Johnson, Covance, WuXi AppTec, Hengrui Pharmaceuticals, Sunshine Lake Pharma, and Chia Tai Tianqing — have purchased this recombinant virus product. From Beijing to Paris, from Guangzhou to Boston, this "Made in China" "AAV mouse hepatitis B model" has become a name recognized and widely used by hepatitis B researchers around the world.

Chapter Seven: Bearing Fruit (2021–2026)

In 2023, Dr. Zhang Liguo's team at the Institute of Biophysics, Chinese Academy of Sciences, published a study in Nature Communications. They first constructed a complex humanized IFNAR mouse model, then used AAV-HBV virus to establish chronic hepatitis B infection in order to evaluate the antiviral efficacy of human interferon. This means the AAV-HBV model has come to be regarded as a "benchmark" for validating the effectiveness of more complex models.

In 2024, a study published in npj Vaccines used the rAAV8-HBV1.3 model to evaluate an mRNA therapeutic vaccine, observing virologic suppression lasting more than 208 days. The AAV-HBV model began entering the cutting-edge field of mRNA vaccines.

In 2026, GSK announced the Phase III clinical trial results for Bepirovirsen. The mechanism of this antisense oligonucleotide drug is precisely to inhibit viral protein synthesis by degrading HBV mRNA — and as early as 2018, GSK scientists had already validated the in vivo effects of similar oligonucleotide drugs on the AAV-HBV model. Professor Hou Jinlin is one of the global principal investigators of this Phase III trial — and in 2018, it was on the AAV-HBV model that he studied the role of IL-21 in antiviral immunity.

The same model, the same Chinese researcher — from basic research to a global Phase III trial — linking together a complete translational medicine chain.

Epilogue: Sixteen Years, a Closed Loop

In 2010, a PhD student of six and a half years, in order not to exceed the time limit for graduation, left a paper in a Chinese journal.

In 2026, the model described in that "disdained" paper became a cornerstone tool of global hepatitis B drug development — widely used by international peers, featured in Nature Communications, and a core data source for reports at the EASL annual conference.

From a preliminary experiment with three mice, to FivePlus's virus product catalog, to GSK's internal R&D pipeline, to the success of a Phase III clinical trial — Dr. Dong Xiaoyan and his AAV-HBV model took sixteen years to complete a full translational medicine loop.

The most moving part of this story is that it was never a carefully designed path. It began with a "failed" attempt, a "give it a try" idea, and a PhD student's pragmatic choice made in order to graduate. It was not published in a top international journal, received no initial international attention, and was even felt by colleagues to be a waste that should be withdrawn. But it survived, because it was good enough to use.

In the end, it changed the world.

On Interests and Patents

When this model first attracted attention from multinational corporations, one major pharmaceutical company offered to purchase the virus at several times the market price, on the condition of a two-year exclusive license that barred supply to any third party.

The offer was tempting, and the revenue it could have generated would have been a much-needed lifeline for FivePlus, which was then severely short of funds. Yet, looking beyond the company's own development, it is the common mindset of cadres trained in the military to analyze issues with a comprehensive, objective, and developmental dialectical perspective and to keep the big picture in mind.

Had the offer been accepted, the most likely outcome would have been the emergence of an exclusive blockbuster product with high-price market monopolization. As a "hepatitis B superpower" with more than 100 million hepatitis B patients, China's health insurance funds would have come under enormous pressure, and the families of nearly 100 million patients would either have lost access to treatment or been forced to bear heavy financial burdens because of the exorbitant drug prices — not to mention patients worldwide. Gilead's exclusive hepatitis C miracle drug sofosbuvir, priced at US$84,000 per week, is a case in point.

After weighing the pros and cons, Dr. Dong declined the high-price offer and insisted on affordable pricing, so that every team capable of designing and developing hepatitis B drugs could afford high-quality, low-cost hepatitis B animal models — a humanistic vision of drug equity. He ultimately even abandoned the patent that had already been filed. As a result, his team's annual revenue from this product over the years has remained in the single-digit millions of RMB, peaking at only 13 million yuan in the best year — an outcome that objectively limited the pace and scale of the company's gene therapy new drug R&D. Today, multiple companies at home and abroad have imitated or even directly copied this technology and product for sale.

Yet today, it is heartening to see the waters of hepatitis B drug development stirred into ripples: many R&D teams at home and abroad have used the AAV8-HBV1.3 and related AAV-HBV mouse models and made highly exciting progress on hepatitis B drugs and therapeutic vaccines, including but not limited to:

• ACT201 (Amoytop Biotech): Antisense oligonucleotide (ASO). In the AAV-HBV model, its inhibitory activity against HBsAg and hepatic exposure levels are superior to those of comparable products (such as GSK's Bepirovirsen), with lower off-target toxicity. Approved for clinical trials in China.
• HRS-5635 (Hengrui Pharmaceuticals): The world's first hepatitis B siRNA drug to enter Phase III, which initiated Phase III clinical trials in China in May 2026.
• GSK5637608 (formerly JNJ-3989) (GSK): An siRNA drug acquired from Johnson & Johnson for US$1 billion in 2024, currently in Phase II clinical trials.
• AHB-137 (Ausper Biopharma): The fastest-progressing domestically developed ASO, which has initiated Phase III registration trials.

Ausper Biopharma's hepatitis B drug pipeline:

• Therapeutic vaccine (researchers: Zixuan Wang et al.): HBsAg vaccine (with CpG 1018S/QS-21 adjuvant). In the rAAV8-HBV1.3 model, it induces robust immune responses and significantly reduces HBsAg levels.
• mRNA vaccine (company not specified): Therapeutic mRNA vaccine. In the rAAV8-HBV1.3 model, it demonstrates sustained viral suppression and strong immunogenicity.
• ALG-072571 (Aligos Therapeutics): Mechanism not specified. In the AAV-HBV model, it significantly reduces serum HBsAg and HBeAg levels.
• YKYY013 (Yuekang Pharmaceutical / Hangzhou Tianlong Pharmaceutical): Double-stranded siRNA. In the AAV-HBV model, it clears HBV DNA and HBsAg, accompanied by HBsAb generation.
• 129G1-IMDQ (researchers: Xinya Ye et al.): A TLR7/8 agonist–antibody conjugate. An HBsAg-targeting antibody conjugated to a TLR7/8 agonist, designed to promote HBsAg clearance.

A Final Word

This story began with an impulse to "give it a try" and a pragmatic choice made in order to graduate, yet through the serendipity of fate it pushed open the door to a cure for hepatitis B. It never ascended the halls of top-tier journals, yet it truly reshaped the landscape of global drug development by being "good enough to use"; it never took the shortcut of high-price monopoly, but with the simple conviction of "health equity" it returned scientific tools to their original purpose of serving human health. Today, this model is not only a "cornerstone" tool in the field of hepatitis B, but also a mirror — reflecting the composure and confidence of Chinese scientists as they move from "technology following" to "solution contributing." It tells us: true scientific breakthroughs are never confined to the numbers game of impact factors, but lie in whether hundreds of millions of patients can see hope drawing nearer; the greatest innovations are often born of a reverence for practicality, not the pursuit of glossy labels. When a Chinese team serves the world with a model that is "good enough to use," what they write is not merely a scientific success story, but a scientific spirit of openness, sharing, and commitment — this, perhaps, is the most profound echo this story leaves for our time.