VXB-241: An Investigational Bivalent Vaccine Candidate for Respiratory Syncytial Virus and Human Metapneumovirus

1. Executive Summary

VXB-241 is an investigational bivalent subunit vaccine candidate engineered to provide protection against Respiratory Syncytial Virus (RSV) and human Metapneumovirus (hMPV). Developed by Vicebio Ltd., VXB-241 leverages the proprietary Molecular Clamp technology, specifically the re-engineered Clamp2 version, originating from The University of Queensland.[1] This technology is designed to stabilize viral fusion proteins in their highly immunogenic prefusion conformation, a key attribute for eliciting robust protective immune responses.[1] VXB-241 is currently undergoing a Phase 1 clinical trial (NCT06556147; ANZCTR ID: ACTRN12624000228202), primarily targeting older adults (60-83 years) with an initial run-in phase in young adults (18-40 years), to assess its safety, reactogenicity, and immunogenicity across various dose levels.[5] Initial data from this pivotal trial are anticipated by mid-2025.[1]

The progression of VXB-241 into human trials, utilizing the re-engineered Clamp2 technology, represents a significant advancement. The first-generation Molecular Clamp, while demonstrating immunogenicity for targets like SARS-CoV-2, encountered a notable obstacle: a component of the clamp (a peptide fragment from HIV gp41) led to cross-reactive antibodies that interfered with some HIV diagnostic assays.[15] This interference, while not posing a direct safety risk to vaccinees, was a considerable barrier to the platform's widespread applicability. Consequently, The University of Queensland (UQ) team, with support from the Coalition for Epidemic Preparedness Innovations (CEPI), undertook a dedicated effort to re-engineer the technology, resulting in Clamp2.[15] Laboratory validation confirmed Clamp2's efficacy across multiple virus families and, crucially, its freedom from the diagnostic interference issue.[15] A subsequent Phase 1 trial of a Clamp2-based SARS-CoV-2 vaccine further substantiated these improvements, showing safety and immunogenicity comparable to an approved vaccine.[20] Vicebio's decision to license and advance VXB-241, a novel and complex bivalent vaccine based on Clamp2, into clinical trials underscores a strong preclinical validation of Clamp2's suitability for these new viral antigens. Successful clinical data from VXB-241 would therefore not only propel this specific vaccine candidate forward but also significantly validate the Clamp2 platform as a de-risked and versatile tool for rapid vaccine development against a range of other viral pathogens, thereby enhancing its potential for future pandemic preparedness and commercial viability.

Furthermore, Vicebio's strategic focus on a bivalent RSV/hMPV vaccine, with plans for a future trivalent candidate (VXB-251, also targeting Parainfluenza Virus 3 (PIV3) [1]), suggests a clear intent to differentiate itself in the evolving respiratory vaccine market. While effective monovalent RSV vaccines for older adults have recently gained approval (e.g., Arexvy, Abrysvo, mRESVIA [13]), hMPV currently lacks any approved vaccine, representing a significant unmet medical need.[29] A combination vaccine offers the advantages of broader protection with a single administration, potentially leading to improved vaccine compliance and addressing the co-circulation of these major respiratory pathogens. If VXB-241 demonstrates robust efficacy against both RSV and hMPV, it could capture a substantial market share by providing a more convenient and comprehensive protective solution than existing RSV-only vaccines, potentially catalyzing a shift towards multivalent respiratory vaccines for adult populations. The development of VXB-241 addresses a critical public health need for combined protection, particularly in vulnerable populations, and aims to offer advantages in immune response quality, manufacturing efficiency, and formulation as a ready-to-use liquid product.

2. Introduction: The Unmet Medical Need for Combined RSV and hMPV Protection

2.1. Burden of Disease: RSV and hMPV

Respiratory Syncytial Virus (RSV) and human Metapneumovirus (hMPV) are common viral pathogens that impose a considerable global health burden, primarily through acute lower respiratory tract infections (LRTIs).[29]

Respiratory Syncytial Virus (RSV) is a ubiquitous virus infecting the lungs and respiratory passages. It is recognized worldwide as a leading cause of LRTIs, particularly bronchiolitis and pneumonia, in infants and young children.[30] The World Health Organization (WHO) estimates that RSV causes over 30 million episodes of acute LRTIs in children under five years of age annually.[32] Beyond early childhood, RSV also poses a significant threat to older adults and individuals with compromised immune systems, often leading to severe illness, exacerbation of underlying chronic conditions (like asthma or COPD), hospitalization, and mortality.[1] In the United States alone, RSV is estimated to cause approximately 177,000 hospitalizations and 14,000 deaths each year in adults aged 65 and older.[31] Transmission occurs primarily through respiratory droplets from coughs or sneezes and contact with contaminated surfaces.[30] RSV infections typically exhibit seasonal patterns, peaking in the fall and winter months in temperate climates.[29]

Human Metapneumovirus (hMPV), though generally causing less severe illness than RSV, is another major contributor to respiratory tract infections across all age groups.[5] Its clinical presentation is similar to RSV, ranging from upper respiratory tract illness to severe bronchiolitis and pneumonia, particularly in young children, the elderly, and immunocompromised individuals.[30] The incidence of hMPV is comparable to that of influenza and parainfluenza viruses.[29] For instance, in 2018, hMPV was estimated to be responsible for 502,000 hospitalizations among children under five globally.[29] In the U.S. adult population aged 65 and older, hMPV accounts for an estimated 140,000 hospitalizations and 8,000 deaths annually.[31] Like RSV, hMPV spreads through respiratory droplets and contact with contaminated surfaces, with seasonal outbreaks often peaking in late winter and early spring, sometimes overlapping with or following RSV season.[29]

The considerable and often overlapping impact of RSV and hMPV, especially in older adults who may experience prolonged periods of risk from one or both viruses, underscores a strong clinical and public health rationale for a bivalent vaccine. Such a vaccine could simplify immunization schedules and enhance protective coverage during the extended respiratory virus season.

2.2. Current Prophylactic Landscape

Preventive strategies for RSV have seen significant advancements, particularly in recent years. For infants, passive immunization with monoclonal antibodies like palivizumab and, more recently, the longer-acting nirsevimab, provides protection.[29] A major breakthrough has been the approval of several RSV vaccines for older adults (typically 60 years and older), including GSK's AREXVY®, Pfizer's ABRYSVO®, and Moderna's mRESVIA®.[13] Pfizer's ABRYSVO® is also approved for maternal immunization during pregnancy to confer passive immunity to newborns.[29] These vaccines predominantly target the RSV fusion (F) protein, stabilized in its prefusion conformation, which is critical for inducing potent neutralizing antibody responses.[29]

In stark contrast, there are currently no approved vaccines or specific prophylactic therapies available for hMPV.[1] This represents a significant unmet medical need, leaving vulnerable populations without specific protection against hMPV-related LRTIs.

2.3. Rationale for a Bivalent RSV/hMPV Vaccine

The development of a bivalent vaccine targeting both RSV and hMPV, such as VXB-241, is driven by several key factors:

• Addressing Co-circulating Pathogens: RSV and hMPV often co-circulate during respiratory seasons, contributing to a substantial cumulative burden of disease.[29]
• Filling the hMPV Prophylaxis Gap: A bivalent vaccine would offer the first specific preventive measure against hMPV.
• Improved Convenience and Compliance: A single vaccine providing protection against two major respiratory pathogens could simplify vaccination schedules for target populations like older adults, potentially leading to better vaccine uptake and compliance compared to administering multiple monovalent vaccines.[1]
• Potential for Enhanced Protection: Addressing both viruses simultaneously could offer more comprehensive respiratory protection during peak seasons.

2.4. VXB-241 and Vicebio Ltd.

VXB-241 is Vicebio Ltd.'s investigational bivalent subunit vaccine candidate specifically designed to induce immunity against both RSV and hMPV by incorporating antigens from both viruses, stabilized by the Molecular Clamp technology.1

Vicebio Ltd. is a biopharmaceutical company, founded with investment from Medicxi, dedicated to developing next-generation vaccines for respiratory viruses.1 The company acquired the exclusive rights to the Molecular Clamp technology through a license from UniQuest, the commercialization arm of The University of Queensland, Australia, where the technology was originally developed.1

3. The Molecular Clamp Technology: A Novel Platform for Vaccine Design

The foundation of VXB-241 lies in the innovative Molecular Clamp platform technology, a proprietary system for designing and producing subunit vaccines.

3.1. Origins and Development at The University of Queensland (UQ)

The Molecular Clamp technology was conceived and pioneered at The University of Queensland by a team of researchers including Professor Paul Young, Professor Daniel Watterson, and Professor Keith Chappell.[1] Professor Chappell's early postdoctoral research, particularly his work on stabilizing the RSV fusion (F) protein in its prefusion conformation, was a critical precursor to the development of this technology.[34] This foundational research underscored the immunological importance of the prefusion structure of viral F proteins. The core concept involved utilizing a highly stable trimerization domain, derived from fusing the heptad repeats of another fusion protein, to lock the target viral glycoprotein ectodomain into its desired prefusion state.[34] This technology is protected by patents (e.g., "Chimeric molecules and uses thereof" WO2018176103A1; US 2020/0040042) and has been exclusively licensed to Vicebio by UniQuest for further development and commercialization.[1]

3.2. Mechanism of Action of the Molecular Clamp

The fundamental principle of the Molecular Clamp technology is to stabilize viral surface glycoproteins, particularly trimeric class I fusion proteins such as the F proteins of RSV and hMPV, in their native, metastable prefusion conformation.[1] Viral fusion proteins undergo significant conformational changes to mediate viral entry into host cells, transitioning from a prefusion to a post-fusion state. The prefusion conformation is crucial because it presents the critical epitopes that are targeted by the most potent neutralizing antibodies produced during natural infection or effective vaccination.[29] However, when these proteins are produced recombinantly as vaccine antigens, they are often unstable and can prematurely adopt the post-fusion conformation, thereby losing or obscuring these key neutralizing epitopes.[33] The Molecular Clamp acts as a scaffold or a "clamp" that locks the viral antigen into this desired prefusion state, ensuring its structural integrity and optimal presentation to the immune system.[15] The clamp itself is a modular trimerization domain designed to promote correct oligomerization of the viral antigen.[34]

3.3. The Re-engineered Clamp2 Technology

The initial iteration of the Molecular Clamp technology, while effective in stabilizing viral antigens and inducing immune responses (as demonstrated with a SARS-CoV-2 vaccine candidate, Sclamp), encountered an unforeseen issue.[15] A peptide component within the original clamp structure, derived from HIV glycoprotein 41 (gp41), led to the production of antibodies in some vaccine recipients that cross-reacted with certain HIV diagnostic assays, resulting in false-positive HIV test results.[15] This diagnostic interference, though not indicative of HIV infection or any direct safety concern for the vaccinee, posed a significant public health and logistical challenge for widespread vaccine deployment.

To address this, the UQ research team, with continued support from CEPI, embarked on re-engineering the platform.[15] This effort led to the development of the "Clamp2" technology, which was specifically designed to eliminate the HIV diagnostic interference while preserving the essential protein stabilization capabilities of the original clamp.[15] Laboratory testing successfully validated Clamp2, demonstrating its equivalence to the original platform in terms of performance across multiple virus families (including influenza virus, Nipah virus, and SARS-CoV-2) and, critically, confirming the absence of the diagnostic interference issue.[15] The successful re-engineering was further underscored by a Phase 1 clinical trial of a Clamp2-based SARS-CoV-2 vaccine, which showed safety and immunogenicity comparable to an already approved vaccine (Novavax's Nuvaxovid), effectively de-risking the Clamp2 platform for future applications.[20] VXB-241, the bivalent RSV/hMPV vaccine candidate, utilizes this improved and validated Clamp2 technology.

3.4. Advantages Conferred by the Molecular Clamp Technology

The Molecular Clamp technology, particularly its Clamp2 iteration, offers several potential advantages for vaccine development:

• Enhanced and Targeted Immunogenicity: By stabilizing the prefusion conformation, the technology aims to present viral antigens to the immune system in a manner that elicits a more potent, specific, and protective immune response, especially the generation of high-titer neutralizing antibodies.[1]
• Broad Applicability: The modular design of the clamp allows it to be applied to a diverse array of viral pathogens that possess class I fusion proteins. This versatility has been demonstrated in preclinical or early clinical studies with viruses from various families, including Paramyxoviridae (RSV, hMPV, Nipah virus), Coronaviridae (SARS-CoV-2, MERS-CoV), Orthomyxoviridae (Influenza A viruses), and Filoviridae (Ebola virus).[1]
• Improved Manufacturability and Scalability: The technology is designed to facilitate high-yield production of stable viral fusion proteins. The clamp component can also function as a universal affinity tag, potentially streamlining downstream purification processes, which could reduce manufacturing complexity and costs.[3] This is crucial for rapid vaccine production during outbreaks or pandemics.
• Enhanced Formulation and Stability: Vaccines developed using this technology are intended to be formulated as ready-to-use liquids, stable at standard refrigeration temperatures (2-8°C). This eliminates the need for freezing, complex cold-chain logistics, or on-site reconstitution, which are significant advantages for vaccine distribution and administration, particularly in resource-limited settings.[1]
• Rapid Response Capability: The platform's design, which allows for the coupling of a pre-validated clamp sequence with the genetic sequence of a new viral target protein, supports accelerated vaccine development timelines. This was a key objective in its funding by CEPI, aiming to contribute to the "100 Days Mission" for pandemic response.[15] The UQ team has actively tested this rapid response capability, for instance, in a challenge to develop a Chapare virus vaccine candidate within 150 days.[24]

These attributes position the Molecular Clamp technology as a promising platform for developing effective vaccines against challenging respiratory viruses like RSV and hMPV, as well as for responding to future pandemic threats.

4. Preclinical Evidence for Molecular Clamp-Based Vaccines

The Molecular Clamp technology, including its re-engineered Clamp2 version, has undergone substantial preclinical evaluation across a range of viral targets, providing a foundation of evidence supporting its potential. While specific, detailed preclinical immunogenicity and efficacy data for the VXB-241 (RSV/hMPV bivalent) candidate itself are not extensively available in the provided documentation beyond general statements of promising preclinical studies [1], the broader preclinical work on the platform and related antigens is informative.

4.1. General Preclinical Validation of the Molecular Clamp Platform

The Molecular Clamp platform has been successfully applied to numerous viral pathogens, demonstrating its versatility. Studies on viruses such as MERS-CoV, Ebola virus, Nipah virus, and various influenza A subtypes have shown that clamp-stabilized antigens generally trimerize efficiently, maintain the critical prefusion conformation, and remain stable under stress conditions (e.g., 40°C for four weeks).[37] In animal models (typically mice and/or ferrets), these clamp-stabilized subunit vaccines, often formulated with adjuvants, have consistently elicited robust neutralizing antibody responses and, where tested, provided protection against viral challenge.[37] For example, clamp-stabilized influenza HA proteins provided robust protection from homologous virus challenge in mice and ferrets, and some cross-protection against heterologous strains.[38] Similarly, MERS-CoV Sclamp and EBOV GPΔMLDclamp vaccines demonstrated protective efficacy in respective animal challenge models.[41] This body of work establishes a strong proof-of-concept for the technology's ability to generate effective subunit vaccine candidates.

4.2. Preclinical Research on RSV and hMPV with Molecular Clamp Technology by UQ Researchers

The Chappell Group at UQ, the originators of the Molecular Clamp technology, has specifically worked on applying this platform to RSV and hMPV.[4] This focus is evident from their project descriptions and publication record.

Key publications involving UQ researchers (Young, Watterson, Chappell) and relevant to RSV Molecular Clamp vaccine development include:

• Isaacs A, Cheung STM, Thakur N, et al. Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates. Viruses. 2021 Sep 28;13(10):1942.[4] This study investigated a combinatorial antigen strategy (FxG) for RSV, incorporating both F and G glycoproteins. The RSV F clamp antigen was designed, and the RSV FxG immunogen was shown to elicit neutralizing antibodies against RSV in mice, although the response was noted as inferior to that of the F protein alone. Importantly, it induced a response against a conserved protective epitope within the G protein, suggesting potential for broader protection. The inventors of the "Molecular Clamp" patent were authors on this paper.
• Isaacs A, Li Z, Cheung STM, et al. Adjuvant Selection for Influenza and RSV Prefusion Subunit Vaccines. Vaccines (Basel). 2021 Jan 20;9(2):71.[4] This research focused on optimizing adjuvant selection for prefusion subunit vaccines, including those for RSV F protein. It highlighted that different adjuvants (e.g., Addavax with QS21, alhydrogel, ALF55) could elicit potent neutralizing antibodies against RSV when paired with prefusion F antigens, underscoring the importance of formulation. The "Molecular Clamp" patent inventors were also authors here, and figures refer to "clamped antigen," indicating the technology's use.
• Professor Paul Young's earlier work with Keith Chappell in José Melero's lab on stabilizing RSV F protein in its prefusion form was a seminal contribution that informed the development of the Molecular Clamp technology itself.[34]

While direct preclinical immunogenicity and efficacy data for the specific VXB-241 bivalent construct are proprietary to Vicebio and not detailed in these publicly accessible academic publications, the foundational research from UQ clearly demonstrates the application of Molecular Clamp principles to RSV antigens and the generation of neutralizing immune responses in animal models. Vicebio's VXB-211, a monovalent RSV vaccine candidate also using Molecular Clamp technology, was reported to be progressing through preclinical development with an objective to start Phase 1 trials in late 2023.[22] This work likely forms part of the preclinical basis for the bivalent VXB-241.

The successful preclinical development of the Clamp2 platform for SARS-CoV-2, which involved demonstrating robust neutralizing antibody titers, T-cell responses, and protection in hamster models without evidence of vaccine-enhanced disease [43], further supports the general safety and immunogenicity potential of the Clamp2 technology that VXB-241 employs.

5. Clinical Development of VXB-241

VXB-241 has entered clinical development with the initiation of a Phase 1 trial. Vicebio announced the commencement of this trial in September 2024, coinciding with a $100 million Series B financing round intended to support and accelerate the development of its multivalent respiratory virus vaccine pipeline, including VXB-241 and the trivalent candidate VXB-251.[1]

5.1. Phase 1 Clinical Trial (NCT06556147 / ANZCTR ID: ACTRN12624000228202)

The ongoing Phase 1 study is a randomized, placebo- and active-controlled, observer-blind, multi-center trial designed to evaluate the safety, reactogenicity, and immunogenicity of VXB-241.[1] Key details of this trial are summarized in Table 1.

Table 1: VXB-241 (NCT06556147 / ANZCTR ID: ACTRN12624000228202) Phase 1 Clinical Trial Key Details

Feature	Details
Official Title	A Phase 1 Randomized, Placebo- and Active-controlled, Observer-blind Study in Older Adults With Run-in...source (HMPV) 7
Trial Identifiers	NCT06556147 1, ANZCTR ID: ACTRN12624000228202 7 (Note: ANZCTR ID reflects the specific registration in Australia/New Zealand, often linked to the global NCT number)
Sponsor	Vicebio Australia Proprietary Limited 7
Phase	Phase 1 1
Study Design	Randomized, Placebo-controlled, Active-controlled (Arexvy), Observer-blind, Dose Escalation (sequential cohorts in Stage 1), Multi-center 5
Target Population	Stage 1 (Run-in): 16 healthy young adults (18-40 years). Stage 2: 120 healthy older adults (60-83 years).5 Good health allows for pre-existing well-controlled, low-impact chronic diseases.6
Sample Size	Total planned: 136-144 participants 5
Interventions & Dosage	VXB-241 (IM): Four dose levels: 60 µg, 120 µg, 240 µg, 480 µg.5 <br> Placebo (IM): Saline or other inert substance.5 <br> Active Comparator (IM): Arexvy (licensed RSV vaccine) 120 µg (for older adults in Stage 2).5 <br> Revaccination (Day 364 for older adults): Approx. 50% of VXB-241 recipients get VXB-241 again (dose TBD based on Year 1 results), approx. 50% get placebo. Arexvy recipients get Arexvy again. Placebo recipients get VXB-241 (dose TBD).5
Primary Outcome Measures	1. Proportion of older adult participants with 1 or more unsolicited Adverse Events (AEs) (up to Day 30 post-first dose).7 <br> 2. Proportion of older adult participants with 1 or more solicited AEs (up to Day 8 post-first dose).7 <br> 3. Geometric Mean Fold Increase (GMFI) of RSV-A, RSV-B, hMPV-A, and hMPV-B serum neutralizing antibody titers in older adults (Baseline to Day 30 post-first dose).7 <br> 4. Ratio of dose-response curves for GMFIs of neutralizing antibodies (Baseline to Day 30 post-first dose).7
Key Secondary Outcome Measures	Longer-term safety (AEs, SAEs, AESIs, PDAEs up to Day 720).7 <br> Changes in hematology and blood chemistry laboratory values.7 <br> Longer-term immunogenicity: GMFI, Geometric Mean Titers (GMTs), and Sero-response Rates (SSR-4, SSR-8) for neutralizing antibodies to RSV-A, RSV-B, hMPV-A, hMPV-B at various timepoints (Day 182, Day 364 post-first dose; Day 394, Day 546, Day 720 post-revaccination).7 <br> GMFI and Geometric Mean Concentrations (GMC) of serum IgG vs. RSV Pre-F and hMPV Pre-F.7
Study Duration & Timelines	Young adults: approx. 6 months. Older adults: approx. 2 years.5 <br> First participant enrolled: August 13, 2024.7 <br> Expected initial data readout: Mid-2025.1 <br> Estimated study completion: May 1, 2027.5
Recruitment Locations	Australia: University of the Sunshine Coast (Morayfield, Sippy Downs, South Brisbane, QLD); Veritus Research (Bayswater, VIC).7

Source: Derived from data in.[1]

The study is designed in two stages. Stage 1 involves sequential dose escalation cohorts for both young and older adults to establish initial safety and tolerability. Stage 2 focuses on older adults, randomizing them to one of the four VXB-241 dose levels, the active comparator (Arexvy, a licensed RSV vaccine), or placebo.[5] A revaccination phase approximately one year later will assess the durability of the immune response and the effect of a booster dose in the older adult cohort.[5]

Key inclusion criteria involve healthy adults within the specified age ranges, capable of providing informed consent and complying with study procedures. Notably, individuals with pre-existing, well-controlled, low-impact chronic diseases are permitted.[6] Exclusion criteria are comprehensive, ruling out individuals with recent RSV/hMPV infection, significant autoimmune diseases, immunodeficiency, severe asthma, history of severe allergic reactions to vaccines, coagulation disorders, recent receipt of immunosuppressive medications or blood products, and participation in other investigational trials.[6]

5.2. Expected Timelines and Future Development

Initial clinical readouts from the Phase 1 study of VXB-241 are anticipated by mid-2025.[1] These data will be crucial in determining the optimal dose for further development and will provide the first human insights into the safety and immunogenicity of this bivalent Molecular Clamp-based vaccine. Successful outcomes would pave the way for larger Phase 2 and Phase 3 trials to confirm efficacy and further characterize the safety profile in broader populations.

Beyond VXB-241, Vicebio's pipeline includes VXB-251, a trivalent vaccine candidate targeting RSV, hMPV, and Parainfluenza Virus 3 (PIV3).[1] The development of VXB-251 will likely leverage learnings from the VXB-241 program and the underlying Molecular Clamp technology.

The progression of VXB-241 is a key step for Vicebio. The company's ability to secure substantial Series B funding ($100 million) underscores investor confidence in the Molecular Clamp technology and the potential of its multivalent vaccine candidates to address unmet needs in respiratory viral disease prevention.[1] The involvement of seasoned industry veterans like Dr. Moncef Slaoui and Khurem Farooq on Vicebio's board further signals the strategic importance and potential of this program.[8]

6. Mechanism of Action of VXB-241

VXB-241 is a subunit vaccine. Its mechanism of action is based on inducing a protective immune response against specific antigens from RSV and hMPV, which are stabilized in their prefusion conformation by the Molecular Clamp technology.[1]

The primary targets for neutralizing antibodies against both RSV and hMPV are their respective fusion (F) glycoproteins. These F proteins are essential for viral entry into host cells and exist in a metastable prefusion state on the virion surface before undergoing a major conformational change to a highly stable post-fusion state to mediate membrane fusion.[29] The prefusion conformation of the F protein harbors the most critical epitopes for eliciting potent neutralizing antibodies.[29]

The Molecular Clamp technology employed in VXB-241 is designed to "lock" the RSV F and hMPV F proteins into this immunogenically optimal prefusion conformation.[1] By presenting these stabilized prefusion F antigens to the host immune system, VXB-241 aims to:

1. Stimulate B cells to produce high titers of neutralizing antibodies specifically targeting the prefusion F proteins of both RSV and hMPV. These antibodies are expected to bind to the viruses and block their entry into host cells, thereby preventing infection or reducing disease severity.
2. Potentially induce T-cell mediated immunity, which can contribute to viral clearance and long-term protection, although the primary focus of subunit vaccines like VXB-241 is typically humoral immunity.

The bivalent nature of VXB-241, incorporating antigens from both RSV and hMPV, is intended to provide simultaneous protection against these two distinct but clinically significant respiratory pathogens.[1] The successful induction of robust and durable neutralizing antibody responses against both viral components will be a key determinant of its clinical efficacy.

7. Regulatory Status

As an investigational product, VXB-241 is currently in Phase 1 clinical development.[1] It has not yet received marketing authorization from any regulatory agency, such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Australian Therapeutic Goods Administration (TGA).

The ongoing Phase 1 trial (NCT06556147 / ANZCTR ID: ACTRN12624000228202) is being conducted under the regulatory oversight appropriate for early-phase clinical studies in the participating regions (e.g., Australia).[7] Successful completion of Phase 1, demonstrating adequate safety and immunogenicity, will be necessary before VXB-241 can advance to larger Phase 2 and Phase 3 trials, which are required for seeking regulatory approval.

While VXB-241 itself is in early clinical stages, other vaccines targeting RSV have recently gained approval from major regulatory bodies like the FDA and EMA for use in older adults and/or pregnant women (e.g., AREXVY®, ABRYSVO®, mRESVIA®).[13] This establishes a regulatory pathway for RSV vaccines, although the bivalent nature of VXB-241 (targeting both RSV and hMPV, for which no vaccine currently exists) may present unique considerations for regulatory agencies. The active comparator arm in the Phase 1 trial using AREXVY® will provide important comparative data relevant to the RSV component.[5]

8. Scientific Publications and Presentations

Detailed scientific publications and conference presentations specifically on the VXB-241 candidate are limited at this early stage of development, as is common for proprietary investigational products in Phase 1. Most available information comes from press releases by Vicebio and clinical trial registry entries.[1]

However, the underlying Molecular Clamp technology, developed at The University of Queensland by Professors Paul Young, Daniel Watterson, and Keith Chappell, has been described in several peer-reviewed publications. These publications often focus on the application of the technology to other viral targets like influenza, SARS-CoV-2, Nipah virus, and also include work on RSV F protein stabilization and adjuvant selection for RSV subunit vaccines.[4]

Key publications from the UQ group relevant to the technology and its application to RSV include:

• Isaacs A, Cheung STM, Thakur N, Jaberolansar N, Young A, Modhiran N, Bailey D, Graham SP, Young PR, Chappell KJ, Watterson D. Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates. Viruses. 2021 Sep 28;13(10):1942. This paper discusses the Molecular Clamp in the context of RSV F and G protein immunogens.[4]
• Isaacs A, Li Z, Cheung STM, Wijesundara DK, McMillan CLD, Modhiran N, Young PR, Ranasinghe C, Watterson D, Chappell KJ. Adjuvant Selection for Influenza and RSV Prefusion Subunit Vaccines. Vaccines (Basel). 2021 Jan 20;9(2):71. This study explores adjuvants for RSV prefusion F subunit vaccines, with authors being inventors of the Molecular Clamp.[4]
• Chappell KJ, Watterson D, Young PR, et al. Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Infect Dis. 2021;21(8):1123-1135. While focused on SARS-CoV-2, this paper details a clinical trial of the first-generation Molecular Clamp vaccine and discusses the HIV diagnostic interference issue that led to the development of Clamp2.[16]
• Young A, Isaacs A, Scott CAP, Modhiran N, et al. A platform technology for generating subunit vaccines against diverse viral pathogens. Front Immunol. 2022 Aug 18;13:963023. This paper describes the application of the Molecular Clamp technology to MERS-CoV, Ebola, Lassa, and Nipah viruses, demonstrating its broad utility.[22]
• McMillan CLD, Cheung STM, Modhiran N, et al. Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses. NPJ Vaccines. 2021 Nov 8;6(1):135. This publication details the use of the Molecular Clamp for influenza vaccine development.[22]

As VXB-241 progresses through clinical trials, data on its specific safety and immunogenicity profile are expected to be presented at scientific conferences and subsequently published in peer-reviewed journals. The initial data readout anticipated in mid-2025 will be a key milestone for such disclosures.[1]

9. Comparative Landscape and Potential Impact

VXB-241 is entering a dynamic field of respiratory vaccine development, particularly for RSV. Its bivalent nature, targeting both RSV and hMPV, is a key differentiator.

9.1. Existing and Pipeline Vaccines for RSV and hMPV

RSV Vaccines:

As previously noted, several monovalent RSV vaccines for older adults are now approved and available, including:

• AREXVY® (GSK): Adjuvanted (AS01E) RSVPreF3 (prefusion F) subunit vaccine.[13] It is also the active comparator in the VXB-241 Phase 1 trial.[5]
• ABRYSVO® (Pfizer): Bivalent (RSV A and B) prefusion F subunit vaccine.[28] Approved for older adults and maternal immunization.
• mRESVIA® (Moderna): mRNA-based vaccine encoding the prefusion F protein.[13]

Other RSV candidates are in various stages of development using diverse platforms (e.g., viral vector, other subunit approaches, live-attenuated).[28]

hMPV and Combined RSV/hMPV Vaccines:

The landscape for hMPV is less mature, with no currently approved vaccines. However, the recognition of hMPV's disease burden has spurred development, primarily in combination with RSV:

• IVX-A12 (Icosavax/AstraZeneca): A bivalent VLP (Virus-Like Particle) vaccine candidate targeting RSV and hMPV prefusion F proteins. It has shown robust immune responses in Phase 2 trials in older adults and is considered Phase 3-ready.[13] This appears to be a direct competitor to VXB-241.
• Moderna: Has explored mRNA-based combination vaccines, including mRNA-1365 (RSV/hMPV), though pediatric development faced safety signal reviews.[29] They also have mRNA-1653 (hMPV/HPIV3).[29]
• Sanofi Pasteur: Has initiated trials for bivalent RSV/hMPV and trivalent RSV/hMPV/HPIV3 mRNA vaccine candidates.[29]
• VXB-251 (Vicebio): Vicebio's own pipeline includes this trivalent candidate targeting RSV, hMPV, and PIV3, also based on the Molecular Clamp technology.[1]
• Other candidates using live-attenuated virus (LAV) platforms are also in early clinical development for HMPV, some in combination with HPIV3.[29]

Table 2: Overview of Selected RSV and Combined RSV/hMPV Vaccine Candidates

Vaccine Candidate (Developer)	Vaccine Type/Technology	Target Pathogen(s)	Current Development Phase (as of early 2025)	Target Population(s)	Key Reported Efficacy/Immunogenicity Highlights (Illustrative)
VXB-241 (Vicebio Ltd.)	Subunit (Molecular Clamp2 stabilized prefusion F)	RSV, hMPV	Phase 1 1	Older Adults, Young Adults (run-in)	Data anticipated mid-2025 1
AREXVY® (GSK)	Adjuvanted Subunit (RSVPreF3 + AS01E)	RSV	Approved	Older Adults (50/60+)	High efficacy against RSV-LRTD (e.g., 82.6% over one season, 67.2% over two seasons) 29
ABRYSVO® (Pfizer)	Subunit (bivalent prefusion F)	RSV	Approved	Older Adults (60+), Pregnant Women	High efficacy against RSV-LRTI in infants via maternal immunization (e.g., 81.8% within 90 days post-birth); Good efficacy in older adults (e.g., 66.7%-85.7% against RSV-LRTD) 29
mRESVIA® (Moderna)	mRNA (prefusion F)	RSV	Approved	Older Adults (60+)	Good efficacy against RSV-LRTD (e.g., 83.7% for ≥2 symptoms) 29
IVX-A12 (Icosavax/AstraZeneca)	VLP (RSV prefusion F, hMPV prefusion F)	RSV, hMPV	Phase 3 Ready 28	Older Adults	Phase 2: Robust immune responses to all RSV and hMPV subgroups 28
mRNA-1365 (Moderna)	mRNA (RSV prefusion F, hMPV prefusion F)	RSV, hMPV	Phase 1 (Pediatric paused) 29	Pediatrics	Pediatric development paused due to potential safety signal (VAERD) 29
VXB-251 (Vicebio Ltd.)	Subunit (Molecular Clamp2)	RSV, hMPV, PIV3	Preclinical/Early Development 1	Older Adults (anticipated)	Leveraging VXB-241 platform
Sanofi Pasteur mRNA candidates	mRNA (F proteins)	RSV/hMPV; RSV/hMPV/HPIV3	Phase 1 29	Not specified	Trials launched in 2024 29

Source: Compiled from.[1] Development phases and highlights are based on information available up to early 2025 as per snippets.

9.2. Potential Advantages and Niche for VXB-241

VXB-241, by leveraging the Molecular Clamp technology, aims to offer several potential advantages:

• Broad Protection: Targeting both RSV and hMPV addresses a wider spectrum of common respiratory illnesses than monovalent RSV vaccines.[1] This is particularly relevant as hMPV lacks any current vaccine.
• Optimized Immunogenicity: The Molecular Clamp's ability to stabilize prefusion F antigens is intended to elicit a strong and specific neutralizing antibody response, which is key for protection.[1]
• Favorable Formulation: The goal of a ready-to-use, liquid formulation stable at 2-8°C offers practical advantages in manufacturing, distribution, and administration over vaccines requiring freezing or on-site reconstitution.[1]
• Manufacturing Efficiency: The technology is also designed for high-yield production and simplified purification, which could translate to cost-effectiveness and scalability.[3]

The primary niche for VXB-241 will likely be in populations where combined protection is most beneficial, such as older adults who are at risk from both RSV and hMPV. If successful, VXB-241 could become a preferred option for adults seeking comprehensive respiratory virus protection, potentially impacting the uptake of existing monovalent RSV vaccines. Its success will depend on demonstrating comparable or superior immunogenicity and safety for the RSV component relative to approved RSV vaccines, alongside robust immunogenicity and clinical benefit for the hMPV component.

9.3. Potential Public Health Impact

The successful development and deployment of a safe and effective bivalent RSV/hMPV vaccine like VXB-241 could have a significant positive impact on public health:

• Reduction in LRTIs: Substantially decrease the incidence of LRTIs caused by these two viruses, particularly in vulnerable older adult populations.[32]
• Decreased Hospitalizations and Mortality: Lower rates of hospital admissions and deaths associated with RSV and hMPV infections.[29]
• Reduced Healthcare Burden: Alleviate the strain on healthcare systems during peak respiratory virus seasons.[32]
• Improved Quality of Life: Enhance the quality of life for older adults and other at-risk individuals by reducing the risk of severe respiratory illness.

The WHO and CDC have highlighted the significant global burden of RSV and the importance of vaccine development.[32] An effective hMPV component in VXB-241 would address a currently unmet need.

10. Challenges and Future Directions

While VXB-241 and the Molecular Clamp technology show considerable promise, several challenges and future directions remain:

• Clinical Efficacy Demonstration: The foremost challenge is demonstrating robust clinical efficacy against both RSV and hMPV disease in larger Phase 2/3 trials, along with a favorable safety profile. The immunogenicity observed in Phase 1 must translate to real-world protection.
• Durability of Protection: The longevity of the immune response and the need for, and timing of, potential booster doses (revaccination is being explored in the Phase 1 trial [5]) will be critical for long-term impact.
• Strain Coverage: Ensuring the vaccine provides broad protection against circulating strains of both RSV (subtypes A and B) and hMPV (subtypes A and B) will be important. The prefusion F target is generally conserved, but viral evolution is a constant consideration.
• Competition: The vaccine landscape, especially for RSV, is becoming increasingly competitive with several approved products and other combination vaccines in development (e.g., AstraZeneca's IVX-A12 [13]). VXB-241 will need to demonstrate clear advantages in terms of efficacy, safety, breadth of protection, or convenience.
• Pediatric Development: While the current Phase 1 trial focuses on adults, RSV and hMPV are major pathogens in infants and young children. Future development may explore pediatric indications, which would require careful safety and efficacy evaluation in these distinct populations, mindful of historical challenges with RSV vaccine development in infants (e.g., VAERD concerns with some platforms [29]).
• Expansion of Multivalency: Vicebio's pipeline includes VXB-251 (RSV/hMPV/PIV3) [1], indicating a strategy towards even broader respiratory protection. The success of VXB-241 will be a stepping stone for these more complex multivalent vaccines.
• Global Access: Ensuring that successful vaccines are accessible globally, including in low- and middle-income countries where the disease burden can be highest, remains a critical public health goal, aligning with CEPI's equitable access policies associated with UQ's technology development.[15]

11. Conclusion

VXB-241 represents a promising step forward in the quest for comprehensive protection against common and impactful respiratory viruses. As a bivalent vaccine candidate targeting both RSV and hMPV, it leverages the advanced, re-engineered Clamp2 Molecular Clamp technology developed at The University of Queensland. This technology aims to overcome previous challenges in subunit vaccine design by stabilizing viral antigens in their most immunogenic prefusion conformation, potentially leading to enhanced protective immune responses, improved manufacturability, and favorable formulation characteristics.

The ongoing Phase 1 clinical trial (NCT06556147 / ANZCTR ID: ACTRN12624000228202) is a critical milestone. Its primary objectives are to establish the safety, reactogenicity, and immunogenicity of VXB-241 in both young and older adults. The inclusion of an active RSV vaccine comparator (Arexvy) and a revaccination schedule will provide valuable insights into VXB-241's relative performance and the durability of the immune response it elicits. The anticipation of initial data by mid-2025 is a key inflection point for Vicebio and the future of this vaccine candidate.

The strategic decision to pursue a bivalent (and subsequently trivalent) vaccine addresses a clear unmet medical need, particularly for hMPV for which no vaccine currently exists, and offers a potentially more convenient and comprehensive approach to respiratory virus prevention in adults compared to existing monovalent RSV vaccines. The significant financial backing secured by Vicebio reflects confidence in this approach and the underlying technology.

Successful clinical development of VXB-241 would not only provide a novel tool against two significant respiratory pathogens but also further validate the Clamp2 platform as a robust and versatile technology for rapid development of vaccines against a wider range of viral threats, contributing to global pandemic preparedness efforts. However, the path to licensure and widespread use will require rigorous demonstration of clinical efficacy and safety in larger trials, navigating a competitive landscape, and addressing questions of long-term protection and strain coverage. The journey of VXB-241 will be closely watched by the scientific, medical, and public health communities.

12. References

32 VXB 241 | VXB-241 Vaccine Against RSV and hMPV. OntoStim.

8 Basic Info. VXB-241. Synapse by PatSnap.

32 VXB 241 | VXB-241 Vaccine Against RSV and hMPV. OntoStim.

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29 Lin, G.-L., et al. (2025). Recent Developments in Respiratory Syncytial Virus and Human Metapneumovirus Vaccines. Vaccines (Basel), 13(6), 569.

5 A Study of RSV-HMPV Bivalent Vaccine VXB-241 in Older Adults. TrialScreen. (NCT06556147).

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46 VXB-241. MedPath. (NCT06556147).

28 RSV Vaccines Approved in the U.S. Vax-Before-Travel.com. March 2025.

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29 Lin, G.-L., et al. (2025). Recent Developments in Respiratory Syncytial Virus and Human Metapneumovirus Vaccines. Vaccines (Basel), 13(6), 569..29

28 Respiratory Syncytial Virus (RSV) Vaccines 2025. Vax-Before-Travel.com. March 2025..28

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24 UQ tests vaccine response in 'moonshot' challenge. The University of Queensland News. April 2025.

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27 Vicebio Secures $100M Series B Funding and Begins Phase 1 RSV/hMPV Vaccine Study. Synapse by PatSnap.

13 Vicebio secures $100m to advance RSV and hMPV vaccine combo to Phase I. Clinical Trials Arena. September 23, 2024..13

15 Scientists take aim at next pandemic threat with new "molecular clamp" rapid response vaccine platform. CEPI. November 25, 2022..15

37 CEPI, University of Queensland and CSL partner to advance development and manufacture of COVID-19 vaccine candidate. CEPI.

16 Chappell, K. J., et al. (2021). Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet Infectious Diseases, 21(8), 1123-1135.

29 Lin, G.-L., et al. (2025). Recent Developments in Respiratory Syncytial Virus and Human Metapneumovirus Vaccines. Vaccines (Basel), 13(6), 569..29

19 ViceBio and the Rapid Response Vaccine Pipeline. AIBN, The University of Queensland.

15 Scientists take aim at next pandemic threat with new "molecular clamp" rapid response vaccine platform. CEPI. November 25, 2022..15

17 A second chance for UQ’s molecular clamp vaccine platform. Lab Online. November 28, 2022.

9 Vicebio Advances Clinical Study of RSV/hMPV Bivalent Vaccine & Strengthens Board with Appointments of World Class Veterans. Vicebio News. Nov 21, 2024.

10 Vicebio Advances Clinical Study of RSV/hMPV Bivalent Vaccine & Strengthens Board with Appointments of World Class Veterans. PR Newswire. Nov 21, 2024.

19 ViceBio and the Rapid Response Vaccine Pipeline. AIBN, The University of Queensland..19

33 CEPI and University of Queensland partner to create rapid response molecular clamp vaccines against emerging infectious diseases. CEPI.

20 Successful clinical trial for re-engineered UQ vaccine. The University of Queensland News. November 23, 2023.

18 Chappell, K. J., et al. (2021). Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet Infectious Diseases, 21(8), 1123-1135..16

6 A Study of RSV-HMPV Bivalent Vaccine VXB-241 in Older Adults. Veeva CTV. (NCT06556147)..6

5 A Study of RSV-HMPV Bivalent Vaccine VXB-241 in Older Adults. TrialScreen. (NCT06556147)..5

21 Scott, C. A. P. (2022). Development of rapid response vaccine and therapeutic platforms for emerging viral diseases. UQ eSpace.

34 Young, P. R. (2020). Disease X ver1. 0: COVID-19. Pathology, 52(5), 481-483.

43 Chappell, K. J., Watterson, D., et al. (2020). Molecular clamp stabilised Spike protein for protection against SARS-CoV-2. bioRxiv. (Preprint, later published).

11 Vaccines developer Vicebio unveiled $100 million in financing... Synapse by PatSnap. (Content derived from press release).

22 Vicebio. AIBN, The University of Queensland. (Project page, lists publications).

38 McMillan CLD, et al. (2021). Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses. NPJ Vaccines, 6(1), 135.

29 Lin, G.-L., et al. (2025). Recent Developments in Respiratory Syncytial Virus and Human Metapneumovirus Vaccines. Vaccines (Basel), 13(6), 569..29

39 McMillan CLD, et al. (2021). Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses. NPJ Vaccines, 6(1), 135..38

41 Young A, Isaacs A, Scott CAP, et al. (2022). A platform technology for generating subunit vaccines against diverse viral pathogens. Frontiers in Immunology, 13, 963023.

2 'A bouquet to immune system': The UQ tech helping Dr Manu Hanon and Vicebio beat the next pandemic. AIBN, The University of Queensland. March 17, 2025.

22 Vicebio. AIBN, The University of Queensland..22

22 Vicebio. AIBN, The University of Queensland..22

42 Dr Andrew Young. AIBN, The University of Queensland. (Profile page, lists publication).

22 Vicebio. AIBN, The University of Queensland..22

45 Professor Keith Chappell. AIBN, The University of Queensland. (Profile page).

12 UK biotech startup raises $100M for next-gen vaccines for respiratory viruses. The Next Web. September 23, 2024.

7 A Phase 1 Randomized, Placebo- and Active-controlled, Observer-blind Study... ANZCTR. (Trial ID: ACTRN12624000228202 / NCT06556147).

21 Scott, C. A. P. (2022). Development of rapid response vaccine and therapeutic platforms for emerging viral diseases. UQ eSpace..21

2 'A bouquet to immune system': The UQ tech helping Dr Manu Hanon and Vicebio beat the next pandemic. AIBN, The University of Queensland. March 17, 2025..2

13 Vicebio secures $100m to advance RSV and hMPV vaccine combo to Phase I. Clinical Trials Arena. September 23, 2024..13

29 Lin, G.-L., et al. (2025). Recent Developments in Respiratory Syncytial Virus and Human Metapneumovirus Vaccines. Vaccines (Basel), 13(6), 569..29

14 Vicebio Announces $100 Million Series B Financing and Initiation of Phase 1 Clinical Study of RSV/hMPV Bivalent Vaccine. PR Newswire. September 23, 2024.

38 McMillan CLD, et al. (2021). Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses. NPJ Vaccines, 6(1), 135..38

43 Chappell, K. J., Watterson, D., et al. (2020). Molecular clamp stabilised Spike protein for protection against SARS-CoV-2. bioRxiv..43

21 Scott, C. A. P. (2022). Development of rapid response vaccine and therapeutic platforms for emerging viral diseases. UQ eSpace..21

1 Vicebio Announces $100 Million Series B Financing and Initiation of Phase 1 Clinical Study of RSV/hMPV Bivalent Vaccine. Vicebio. September 23, 2024..1

13 Vicebio secures $100m to advance RSV and hMPV vaccine combo to Phase I. Clinical Trials Arena. September 23, 2024..13

29 Lin, G.-L., et al. (2025). Recent Developments in Respiratory Syncytial Virus and Human Metapneumovirus Vaccines. Vaccines (Basel), 13(6), 569..29

24 UQ tests vaccine response in 'moonshot' challenge. The University of Queensland News. April 2025..24

3 Vicebio - Technology, Pipeline, News, Contact. Vicebio.

23 Scientists take aim at next pandemic threat with new "molecular clamp" rapid response vaccine platform. CEPI. November 25, 2022..15

24 UQ tests vaccine response in 'moonshot' challenge. The University of Queensland News. April 2025..24

4 Vicebio Technology page (with publication links). Vicebio.

31 Vicebio Pipeline page. Vicebio.

35 Isaacs A, Cheung STM, Thakur N, et al. (2021). Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates. Viruses, 13(10), 1942..22

36 Isaacs A, Li Z, Cheung STM, et al. (2021). Adjuvant Selection for Influenza and RSV Prefusion Subunit Vaccines. Vaccines (Basel), 9(2), 71..22

19 Vicebio project page. AIBN, The University of Queensland..22

17 A second chance for UQ’s molecular clamp vaccine platform. Lab Online. November 28, 2022..17

47 Vicebio News page. Vicebio.

4 Vicebio Technology page. Vicebio..4

34 Young, P. R. (2020). Disease X ver1. 0: COVID-19. Pathology, 52(5), 481-483..34

40 McMillan CLD, et al. (2021). Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses. NPJ Vaccines, 6(1), 135..38

44 Young A, Isaacs A, Scott CAP, et al. (2022). A platform technology for generating subunit vaccines against diverse viral pathogens. Frontiers in Immunology, 13, 963023..41

22 Vicebio project page. AIBN, The University of Queensland..22

22 Vicebio project page. AIBN, The University of Queensland..22

47 Vicebio News page. Vicebio..47

7 A Phase 1 Randomized, Placebo- and Active-controlled, Observer-blind Study... ANZCTR. (Trial ID: ACTRN12624000228202 / NCT06556147)..7

22 Vicebio project page. AIBN, The University of Queensland..22

48 Vicebio website check. Vicebio. (General check, specific content not detailed).

[21]# VXB-241: An Investigational Bivalent Vaccine Candidate for Respiratory Syncytial Virus and Human Metapneumovirus

1. Executive Summary

VXB-241 is an investigational bivalent subunit vaccine candidate engineered to provide protection against Respiratory Syncytial Virus (RSV) and human Metapneumovirus (hMPV). Developed by Vicebio Ltd., VXB-241 leverages the proprietary Molecular Clamp technology, specifically the re-engineered Clamp2 version, originating from The University of Queensland.[1] This technology is designed to stabilize viral fusion proteins in their highly immunogenic prefusion conformation, a key attribute for eliciting robust protective immune responses.[1] VXB-241 is currently undergoing a Phase 1 clinical trial (NCT06556147; ANZCTR ID: ACTRN12624000228202), primarily targeting older adults (60-83 years) with an initial run-in phase in young adults (18-40 years), to assess its safety, reactogenicity, and immunogenicity across various dose levels.[5] Initial data from this pivotal trial are anticipated by mid-2025.[1]

The progression of VXB-241 into human trials, utilizing the re-engineered Clamp2 technology, represents a significant advancement. The first-generation Molecular Clamp, while demonstrating immunogenicity for targets like SARS-CoV-2, encountered a notable obstacle: a component of the clamp (a peptide fragment from HIV gp41) led to cross-reactive antibodies that interfered with some HIV diagnostic assays.[15] This interference, while not posing a direct safety risk to vaccinees, was a considerable barrier to the platform's widespread applicability. Consequently, The University of Queensland (UQ) team, with support from the Coalition for Epidemic Preparedness Innovations (CEPI), undertook a dedicated effort to re-engineer the technology, resulting in Clamp2.[15] Laboratory validation confirmed Clamp2's efficacy across multiple virus families and, crucially, its freedom from the diagnostic interference issue.[15] A subsequent Phase 1 trial of a Clamp2-based SARS-CoV-2 vaccine further substantiated these improvements, showing safety and immunogenicity comparable to an approved vaccine.[20] Vicebio's decision to license and advance VXB-241, a novel and complex bivalent vaccine based on Clamp2, into clinical trials underscores a strong preclinical validation of Clamp2's suitability for these new viral antigens. Successful clinical data from VXB-241 would therefore not only propel this specific vaccine candidate forward but also significantly validate the Clamp2 platform as a de-risked and versatile tool for rapid vaccine development against a range of other viral pathogens, thereby enhancing its potential for future pandemic preparedness and commercial viability.

Furthermore, Vicebio's strategic focus on a bivalent RSV/hMPV vaccine, with plans for a future trivalent candidate (VXB-251, also targeting Parainfluenza Virus 3 (PIV3) [1]), suggests a clear intent to differentiate itself in the evolving respiratory vaccine market. While effective monovalent RSV vaccines for older adults have recently gained approval (e.g., Arexvy, Abrysvo, mRESVIA [13]), hMPV currently lacks any approved vaccine, representing a significant unmet medical need.[29] A combination vaccine offers the advantages of broader protection with a single administration, potentially leading to improved vaccine compliance and addressing the co-circulation of these major respiratory pathogens. If VXB-241 demonstrates robust efficacy against both RSV and hMPV, it could capture a substantial market share by providing a more convenient and comprehensive protective solution than existing RSV-only vaccines, potentially catalyzing a shift towards multivalent respiratory vaccines for adult populations. The development of VXB-241 addresses a critical public health need for combined protection, particularly in vulnerable populations, and aims to offer advantages in immune response quality, manufacturing efficiency, and formulation as a ready-to-use liquid product.

2. Introduction: The Unmet Medical Need for Combined RSV and hMPV Protection

2.1. Burden of Disease: RSV and hMPV

Respiratory Syncytial Virus (RSV) and human Metapneumovirus (hMPV) are common viral pathogens that impose a considerable global health burden, primarily through acute lower respiratory tract infections (LRTIs).[29]

Respiratory Syncytial Virus (RSV) is a ubiquitous virus infecting the lungs and respiratory passages. It is recognized worldwide as a leading cause of LRTIs, particularly bronchiolitis and pneumonia, in infants and young children.[30] The World Health Organization (WHO) estimates that RSV causes over 30 million episodes of acute LRTIs in children under five years of age annually.[32] Beyond early childhood, RSV also poses a significant threat to older adults and individuals with compromised immune systems, often leading to severe illness, exacerbation of underlying chronic conditions (like asthma or COPD), hospitalization, and mortality.[1] In the United States alone, RSV is estimated to cause approximately 177,000 hospitalizations and 14,000 deaths each year in adults aged 65 and older.[31] Transmission occurs primarily through respiratory droplets from coughs or sneezes and contact with contaminated surfaces.[30] RSV infections typically exhibit seasonal patterns, peaking in the fall and winter months in temperate climates.[29]

Human Metapneumovirus (hMPV), though generally causing less severe illness than RSV, is another major contributor to respiratory tract infections across all age groups.[29] Its clinical presentation is similar to RSV, ranging from upper respiratory tract illness to severe bronchiolitis and pneumonia, particularly in young children, the elderly, and immunocompromised individuals.[30] The incidence of hMPV is comparable to that of influenza and parainfluenza viruses.[29] For instance, in 2018, hMPV was estimated to be responsible for 502,000 hospitalizations among children under five globally.[29] In the U.S. adult population aged 65 and older, hMPV accounts for an estimated 140,000 hospitalizations and 8,000 deaths annually.[31] Like RSV, hMPV spreads through respiratory droplets and contact with contaminated surfaces, with seasonal outbreaks often peaking in late winter and early spring, sometimes overlapping with or following RSV season.[29]

The considerable and often overlapping impact of RSV and hMPV, especially in older adults who may experience prolonged periods of risk from one or both viruses, underscores a strong clinical and public health rationale for a bivalent vaccine. Such a vaccine could simplify immunization schedules and enhance protective coverage during the extended respiratory virus season.

2.2. Current Prophylactic Landscape

Preventive strategies for RSV have seen significant advancements, particularly in recent years. For infants, passive immunization with monoclonal antibodies like palivizumab and, more recently, the longer-acting nirsevimab, provides protection.[29] A major breakthrough has been the approval of several RSV vaccines for older adults (typically 60 years and older), including GSK's AREXVY®, Pfizer's ABRYSVO®, and Moderna's mRESVIA®.[28] Pfizer's ABRYSVO® is also approved for maternal immunization during pregnancy to confer passive immunity to newborns.[29] These vaccines predominantly target the RSV fusion (F) protein, stabilized in its prefusion conformation, which is critical for inducing potent neutralizing antibody responses.[29]

In stark contrast, there are currently no approved vaccines or specific prophylactic therapies available for hMPV.[1] This represents a significant unmet medical need, leaving vulnerable populations without specific protection against hMPV-related LRTIs.

2.3. Rationale for a Bivalent RSV/hMPV Vaccine

The development of a bivalent vaccine targeting both RSV and hMPV, such as VXB-241, is driven by several key factors:

• Addressing Co-circulating Pathogens: RSV and hMPV often co-circulate during respiratory seasons, contributing to a substantial cumulative burden of disease.[29]
• Filling the hMPV Prophylaxis Gap: A bivalent vaccine would offer the first specific preventive measure against hMPV.
• Improved Convenience and Compliance: A single vaccine providing protection against two major respiratory pathogens could simplify vaccination schedules for target populations like older adults, potentially leading to better vaccine uptake and compliance compared to administering multiple monovalent vaccines.[1]
• Potential for Enhanced Protection: Addressing both viruses simultaneously could offer more comprehensive respiratory protection during peak seasons.

2.4. VXB-241 and Vicebio Ltd.

VXB-241 is Vicebio Ltd.'s investigational bivalent subunit vaccine candidate specifically designed to induce immunity against both RSV and hMPV by incorporating antigens from both viruses, stabilized by the Molecular Clamp technology.1

Vicebio Ltd. is a biopharmaceutical company, founded with investment from Medicxi, dedicated to developing next-generation vaccines for respiratory viruses.1 The company acquired the exclusive rights to the Molecular Clamp technology through a license from UniQuest, the commercialization arm of The University of Queensland, Australia, where the technology was originally developed.1

3. The Molecular Clamp Technology: A Novel Platform for Vaccine Design

The foundation of VXB-241 lies in the innovative Molecular Clamp platform technology, a proprietary system for designing and producing subunit vaccines.

3.1. Origins and Development at The University of Queensland (UQ)

The Molecular Clamp technology was conceived and pioneered at The University of Queensland by a team of researchers including Professor Paul Young, Professor Daniel Watterson, and Professor Keith Chappell.[1] Professor Chappell's early postdoctoral research, particularly his work on stabilizing the RSV fusion (F) protein in its prefusion conformation, was a critical precursor to the development of this technology.[34] This foundational research underscored the immunological importance of the prefusion structure of viral F proteins. The core concept involved utilizing a highly stable trimerization domain, derived from fusing the heptad repeats of another fusion protein, to lock the target viral glycoprotein ectodomain into its desired prefusion state.[34] This technology is protected by patents (e.g., "Chimeric molecules and uses thereof" WO2018176103A1; US 2020/0040042) and has been exclusively licensed to Vicebio by UniQuest for further development and commercialization.[1]

3.2. Mechanism of Action of the Molecular Clamp

The fundamental principle of the Molecular Clamp technology is to stabilize viral surface glycoproteins, particularly trimeric class I fusion proteins such as the F proteins of RSV and hMPV, in their native, metastable prefusion conformation.[1] Viral fusion proteins undergo significant conformational changes to mediate viral entry into host cells, transitioning from a prefusion to a post-fusion state. The prefusion conformation is crucial because it presents the critical epitopes that are targeted by the most potent neutralizing antibodies produced during natural infection or effective vaccination.[29] However, when these proteins are produced recombinantly as vaccine antigens, they are often unstable and can prematurely adopt the post-fusion conformation, thereby losing or obscuring these key neutralizing epitopes.[33] The Molecular Clamp acts as a scaffold or a "clamp" that locks the viral antigen into this desired prefusion state, ensuring its structural integrity and optimal presentation to the immune system.[15] The clamp itself is a modular trimerization domain designed to promote correct oligomerization of the viral antigen.[34]

3.3. The Re-engineered Clamp2 Technology

The initial iteration of the Molecular Clamp technology, while effective in stabilizing viral antigens and inducing immune responses (as demonstrated with a SARS-CoV-2 vaccine candidate, Sclamp), encountered an unforeseen issue.[15] A peptide component within the original clamp structure, derived from HIV glycoprotein 41 (gp41), led to the production of antibodies in some vaccine recipients that cross-reacted with certain HIV diagnostic assays, resulting in false-positive HIV test results.[15] This diagnostic interference, though not indicative of HIV infection or any direct safety concern for the vaccinee, posed a significant public health and logistical challenge for widespread vaccine deployment.

To address this, the UQ research team, with continued support from CEPI, embarked on re-engineering the platform.[15] This effort led to the development of the "Clamp2" technology, which was specifically designed to eliminate the HIV diagnostic interference while preserving the essential protein stabilization capabilities of the original clamp.[15] Laboratory testing successfully validated Clamp2, demonstrating its equivalence to the original platform in terms of performance across multiple virus families (including influenza virus, Nipah virus, and SARS-CoV-2) and, critically, confirming the absence of the diagnostic interference issue.[15] The successful re-engineering was further underscored by a Phase 1 clinical trial of a Clamp2-based SARS-CoV-2 vaccine, which showed safety and immunogenicity comparable to an already approved vaccine (Novavax's Nuvaxovid), effectively de-risking the Clamp2 platform for future applications.[20] VXB-241, the bivalent RSV/hMPV vaccine candidate, utilizes this improved and validated Clamp2 technology.

3.4. Advantages Conferred by the Molecular Clamp Technology

The Molecular Clamp technology, particularly its Clamp2 iteration, offers several potential advantages for vaccine development:

• Enhanced and Targeted Immunogenicity: By stabilizing the prefusion conformation, the technology presents viral antigens to the immune system in a manner that optimally elicits highly specific and robust protective immune responses, particularly neutralizing antibodies.[1]
• Broad Applicability: The platform's modular nature allows it to be applied to a wide range of viral pathogens, including those from diverse families such as Paramyxoviridae (RSV, hMPV, Nipah), Coronaviridae (SARS-CoV-2, MERS-CoV), Orthomyxoviridae (Influenza), and Filoviridae (Ebola).[1]
• Improved Manufacturability: The technology is designed for high-yield production of stable viral fusion proteins. The clamp can also serve as a universal affinity tag, streamlining purification processes and potentially reducing manufacturing costs.[3]
• Enhanced Formulation and Stability: Vaccines developed using this technology are intended for ready-to-use liquid formulations, stable at standard refrigeration temperatures (2-8°C), eliminating the need for freezing or complex on-site reconstitution.[1]
• Rapid Response Capability: The platform's design, which allows for the coupling of a pre-validated clamp sequence with the genetic sequence of a new viral target protein, supports accelerated vaccine development timelines. This was a key objective in its funding by CEPI, aiming to contribute to the "100 Days Mission" for pandemic response.[15] The UQ team has actively tested this rapid response capability, for instance, in a challenge to develop a Chapare virus vaccine candidate within 150 days.[24]

These attributes position the Molecular Clamp technology as a promising platform for developing effective vaccines against challenging respiratory viruses like RSV and hMPV, as well as for responding to future pandemic threats.

4. Preclinical Evidence for Molecular Clamp-Based Vaccines

The Molecular Clamp technology, including its re-engineered Clamp2 version, has undergone substantial preclinical evaluation across a range of viral targets, providing a foundation of evidence supporting its potential. While specific, detailed preclinical immunogenicity and efficacy data for the VXB-241 (RSV/hMPV bivalent) candidate itself are not extensively available in the provided documentation beyond general statements of promising preclinical studies [1], the broader preclinical work on the platform and related antigens is informative.

4.1. General Preclinical Validation of the Molecular Clamp Platform

The Molecular Clamp platform has been successfully applied to numerous viral pathogens, demonstrating its versatility. Studies on viruses such as MERS-CoV, Ebola virus, Nipah virus, and various influenza A subtypes have shown that clamp-stabilized antigens generally trimerize efficiently, maintain the critical prefusion conformation, and remain stable under stress conditions (e.g., 40°C for four weeks).[37] In animal models (typically mice and/or ferrets), these clamp-stabilized subunit vaccines, often formulated with adjuvants, have consistently elicited robust neutralizing antibody responses and, where tested, provided protection against viral challenge.[37] For example, clamp-stabilized influenza HA proteins provided robust protection from homologous virus challenge in mice and ferrets, and some cross-protection against heterologous strains.[38] Similarly, MERS-CoV Sclamp and EBOV GPΔMLDclamp vaccines demonstrated protective efficacy in respective animal challenge models.[41] This body of work establishes a strong proof-of-concept for the technology's ability to generate effective subunit vaccine candidates.

4.2. Preclinical Research on RSV and hMPV with Molecular Clamp Technology by UQ Researchers

The Chappell Group at UQ, the originators of the Molecular Clamp technology, has specifically worked on applying this platform to RSV and hMPV.[4] This focus is evident from their project descriptions and publication record.

Key publications involving UQ researchers (Young, Watterson, Chappell) and relevant to RSV Molecular Clamp vaccine development include:

• Isaacs A, Cheung STM, Thakur N, et al. Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates. Viruses. 2021 Sep 28;13(10):1942.[4] This study investigated a combinatorial antigen strategy (FxG) for RSV, incorporating both F and G glycoproteins. The RSV F clamp antigen was designed, and the RSV FxG immunogen was shown to elicit neutralizing antibodies against RSV in mice, although the response was noted as inferior to that of the F protein alone. Importantly, it induced a response against a conserved protective epitope within the G protein, suggesting potential for broader protection. The inventors of the "Molecular Clamp" patent were authors on this paper.
• Isaacs A, Li Z, Cheung STM, et al. Adjuvant Selection for Influenza and RSV Prefusion Subunit Vaccines. Vaccines (Basel). 2021 Jan 20;9(2):71.[4] This research focused on optimizing adjuvant selection for prefusion subunit vaccines, including those for RSV F protein. It highlighted that different adjuvants (e.g., Addavax with QS21, alhydrogel, ALF55) could elicit potent neutralizing antibodies against RSV when paired with prefusion F antigens, underscoring the importance of formulation. The "Molecular Clamp" patent inventors were also authors here, and figures refer to "clamped antigen," indicating the technology's use.
• Professor Paul Young's earlier work with Keith Chappell in José Melero's lab on stabilizing RSV F protein in its prefusion form was a seminal contribution that informed the development of the Molecular Clamp technology itself.[34]

While direct preclinical immunogenicity and efficacy data for the specific VXB-241 bivalent construct are proprietary to Vicebio and not detailed in these publicly accessible academic publications, the foundational research from UQ clearly demonstrates the application of Molecular Clamp principles to RSV antigens and the generation of neutralizing immune responses in animal models. Vicebio's VXB-211, a monovalent RSV vaccine candidate also using Molecular Clamp technology, was reported to be progressing through preclinical development with an objective to start Phase 1 trials in late 2023.[22] This work likely forms part of the preclinical basis for the bivalent VXB-241.

The successful preclinical development of the Clamp2 platform for SARS-CoV-2, which involved demonstrating robust neutralizing antibody titers, T-cell responses, and protection in hamster models without evidence of vaccine-enhanced disease [43], further supports the general safety and immunogenicity potential of the Clamp2 technology that VXB-241 employs.

5. Clinical Development of VXB-241

VXB-241 has entered clinical development with the initiation of a Phase 1 trial. Vicebio announced the commencement of this trial in September 2024, coinciding with a $100 million Series B financing round intended to support and accelerate the development of its multivalent respiratory virus vaccine pipeline, including VXB-241 and the trivalent candidate VXB-251.[1]

5.1. Phase 1 Clinical Trial (NCT06556147 / ANZCTR ID: ACTRN12624000228202)

The ongoing Phase 1 study is a randomized, placebo- and active-controlled, observer-blind, multi-center trial designed to evaluate the safety, reactogenicity, and immunogenicity of VXB-241.[1] Key details of this trial are summarized in Table 1.

Table 1: VXB-241 (NCT06556147 / ANZCTR ID: ACTRN12624000228202) Phase 1 Clinical Trial Key Details

Feature	Details
Official Title	A Phase 1 Randomized, Placebo- and Active-controlled, Observer-blind...source (RSV) And Human Metapneumovirus (HMPV) 7
Trial Identifiers	NCT06556147 1, ANZCTR ID: ACTRN12624000228202 7
Sponsor	Vicebio Australia Proprietary Limited 7
Phase	Phase 1 1
Study Design	Randomized, Placebo-controlled, Active-controlled (Arexvy), Observer-blind, Dose Escalation (sequential cohorts in Stage 1), Multi-center 5
Target Population	Stage 1 (Run-in): 16 healthy young adults (18-40 years). Stage 2: 120 healthy older adults (60-83 years).5 Good health allows for pre-existing well-controlled, low-impact chronic diseases.6
Sample Size	Total planned: 136-144 participants 5
Interventions & Dosage	VXB-241 (IM): Four dose levels: 60 µg, 120 µg, 240 µg, 480 µg.5 <br> Placebo (IM): Saline or other inert substance.5 <br> Active Comparator (IM): Arexvy (licensed RSV vaccine) 120 µg (for older adults in Stage 2).5 <br> Revaccination (Day 364 for older adults): Approx. 50% of VXB-241 recipients get VXB-241 again (dose TBD based on Year 1 results), approx. 50% get placebo. Arexvy recipients get Arexvy again. Placebo recipients get VXB-241 (dose TBD).5
Primary Outcome Measures	1. Proportion of older adult participants with 1 or more unsolicited Adverse Events (AEs) (up to Day 30 post-first dose).7 <br> 2. Proportion of older adult participants with 1 or more solicited AEs (up to Day 8 post-first dose).7 <br> 3. Geometric Mean Fold Increase (GMFI) of RSV-A, RSV-B, hMPV-A, and hMPV-B serum neutralizing antibody titers in older adults (Baseline to Day 30 post-first dose).7 <br> 4. Ratio of dose-response curves for GMFIs of neutralizing antibodies (Baseline to Day 30 post-first dose).7
Key Secondary Outcome Measures	Longer-term safety (AEs, SAEs, AESIs, PDAEs up to Day 720).7 <br> Changes in hematology and blood chemistry laboratory values.7 <br> Longer-term immunogenicity: GMFI, Geometric Mean Titers (GMTs), and Sero-response Rates (SSR-4, SSR-8) for neutralizing antibodies to RSV-A, RSV-B, hMPV-A, hMPV-B at various timepoints (Day 182, Day 364 post-first dose; Day 394, Day 546, Day 720 post-revaccination).7 <br> GMFI and Geometric Mean Concentrations (GMC) of serum IgG vs. RSV Pre-F and hMPV Pre-F.7
Study Duration & Timelines	Young adults: approx. 6 months. Older adults: approx. 2 years.5 <br> First participant enrolled: August 13, 2024.7 <br> Expected initial data readout: Mid-2025.1 <br> Estimated study completion: May 1, 2027.5
Recruitment Locations	Australia: University of the Sunshine Coast (Morayfield, Sippy Downs, South Brisbane, QLD); Veritus Research (Bayswater, VIC).7

Source: Derived from data in.[1]

The study is designed in two stages. Stage 1 involves sequential dose escalation cohorts for both young and older adults to establish initial safety and tolerability. Stage 2 focuses on older adults, randomizing them to one of the four VXB-241 dose levels, the active comparator (Arexvy, a licensed RSV vaccine), or placebo.[5] A revaccination phase approximately one year later will assess the durability of the immune response and the effect of a booster dose in the older adult cohort.[5]

Key inclusion criteria involve healthy adults within the specified age ranges, capable of providing informed consent and complying with study procedures. Notably, individuals with pre-existing, well-controlled, low-impact chronic diseases are permitted.[6] Exclusion criteria are comprehensive, ruling out individuals with recent RSV/hMPV infection, significant autoimmune diseases, immunodeficiency, severe asthma, history of severe allergic reactions to vaccines, coagulation disorders, recent receipt of immunosuppressive medications or blood products, and participation in other investigational trials.[6]

5.2. Expected Timelines and Future Development

Initial clinical readouts from the Phase 1 study of VXB-241 are anticipated by mid-2025.[1] These data will be crucial in determining the optimal dose for further development and will provide the first human insights into the safety and immunogenicity of this bivalent Molecular Clamp-based vaccine. Successful outcomes would pave the way for larger Phase 2 and Phase 3 trials to confirm efficacy and further characterize the safety profile in broader populations.

Beyond VXB-241, Vicebio's pipeline includes VXB-251, a trivalent vaccine candidate targeting RSV, hMPV, and Parainfluenza Virus 3 (PIV3).[1] The development of VXB-251 will likely leverage learnings from the VXB-241 program and the underlying Molecular Clamp technology.

The progression of VXB-241 is a key step for Vicebio. The company's ability to secure substantial Series B funding ($100 million) underscores investor confidence in the Molecular Clamp technology and the potential of its multivalent vaccine candidates to address unmet needs in respiratory viral disease prevention.[1] The involvement of seasoned industry veterans like Dr. Moncef Slaoui and Khurem Farooq on Vicebio's board further signals the strategic importance and potential of this program.[8]

6. Mechanism of Action of VXB-241

VXB-241 is a subunit vaccine. Its mechanism of action is based on inducing a protective immune response against specific antigens from RSV and hMPV, which are stabilized in their prefusion conformation by the Molecular Clamp technology.[1]

The primary targets for neutralizing antibodies against both RSV and hMPV are their respective fusion (F) glycoproteins. These F proteins are essential for viral entry into host cells and exist in a metastable prefusion state on the virion surface before undergoing a major conformational change to a highly stable post-fusion state to mediate membrane fusion.[29] The prefusion conformation of the F protein harbors the most critical epitopes for eliciting potent neutralizing antibodies.[29]

The Molecular Clamp technology employed in VXB-241 is designed to "lock" the RSV F and hMPV F proteins into this immunogenically optimal prefusion conformation.[1] By presenting these stabilized prefusion F antigens to the host immune system, VXB-241 aims to:

1. Stimulate B cells to produce high titers of neutralizing antibodies specifically targeting the prefusion F proteins of both RSV and hMPV. These antibodies are expected to bind to the viruses and block their entry into host cells, thereby preventing infection or reducing disease severity.
2. Potentially induce T-cell mediated immunity, which can contribute to viral clearance and long-term protection, although the primary focus of subunit vaccines like VXB-241 is typically humoral immunity.

The bivalent nature of VXB-241, incorporating antigens from both RSV and hMPV, is intended to provide simultaneous protection against these two distinct but clinically significant respiratory pathogens.[1] The successful induction of robust and durable neutralizing antibody responses against both viral components will be a key determinant of its clinical efficacy.

7. Regulatory Status

As an investigational product, VXB-241 is currently in Phase 1 clinical development.[1] It has not yet received marketing authorization from any regulatory agency

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