V350A: An Investigational Epstein-Barr Virus Vaccine Candidate – Development Status and Clinical Evaluation

1. Executive Summary

V350A is an investigational prophylactic vaccine candidate designed to protect against Epstein-Barr Virus (EBV) infection and its associated diseases. This vaccine is being co-developed by Merck Sharp & Dohme LLC (Merck) and ModeX Therapeutics, an OPKO Health company.[1] V350A is a component of the broader MDX2201 vaccine program, which employs an innovative ferritin nanoparticle platform technology. This platform is engineered to present multiple EBV antigens—specifically glycoprotein 350 (gp350), glycoprotein H (gH), glycoprotein L (gL), and glycoprotein 42 (gp42)—to the immune system, with the objective of eliciting a robust and broadly neutralizing antibody response.[3]

Currently, V350A, alongside a related candidate designated V350B, is undergoing Phase 1 clinical evaluation in trial NCT06655324. This study aims to assess the safety, tolerability, and immunogenicity of the vaccine candidates in healthy adult volunteers.[6] The development of an effective EBV vaccine is a significant undertaking, driven by the substantial unmet medical need stemming from EBV's widespread prevalence and its etiological links to infectious mononucleosis, various malignancies (including B cell lymphomas and nasopharyngeal carcinoma), and autoimmune diseases such as multiple sclerosis.[2] At present, no approved vaccine against EBV exists.[2]

The scientific foundation for the V350A/MDX2201 program is supported by preclinical research, notably including findings published in Science Translational Medicine in May 2022, which investigated the efficacy of a multi-antigen nanoparticle approach for EBV.[3] The collaboration between Merck, a global pharmaceutical leader, and ModeX Therapeutics, a biotechnology company with a specialized vaccine platform, exemplifies a strategic approach to vaccine development. This partnership combines ModeX's innovative antigen presentation technology with Merck's extensive experience in clinical development, regulatory affairs, and commercialization.[2] The focus on a multi-antigen vaccine design, incorporating gp350, gH, gL, and gp42, reflects an evolution from earlier EBV vaccine strategies that often targeted gp350 alone. This advanced approach aims to induce a more comprehensive immune response capable of neutralizing the virus through multiple mechanisms and inhibiting its entry into different host cell types.[2]

2. Introduction: The Epstein-Barr Virus (EBV) and the Need for a Vaccine

Pathology and Epidemiology of EBV

Epstein-Barr Virus (EBV), a member of the herpesvirus family (human herpesvirus 4), is one of the most common human viruses, with estimates suggesting that over 90% of the adult population worldwide has been infected.[2] Primary infection often occurs in childhood and is typically asymptomatic or results in mild, nonspecific symptoms. However, when primary infection is delayed until adolescence or young adulthood, it frequently manifests as infectious mononucleosis, a debilitating acute illness characterized by fever, pharyngitis, lymphadenopathy, and profound fatigue.[6] Following primary infection, EBV establishes a lifelong latent infection, primarily within B lymphocytes, with periodic reactivation and shedding, typically in oropharyngeal secretions.[13]

Associated Diseases

Beyond infectious mononucleosis, EBV has been etiologically linked to a spectrum of more severe health conditions. It is recognized as a human oncogenic virus, contributing to the development of various B cell lymphomas (such as Burkitt's lymphoma, Hodgkin's lymphoma, and post-transplant lymphoproliferative disorder), T cell lymphomas, NK cell lymphomas, and epithelial cell malignancies, including nasopharyngeal carcinoma and certain types of gastric cancer.[4] More recently, a substantial body of epidemiological and mechanistic evidence has strongly implicated EBV infection as a critical prerequisite and significant risk factor for the development of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system.[2] This association has intensified the interest in developing preventive strategies against EBV.

Current Landscape and Unmet Medical Need

Despite its ubiquitous nature and association with significant morbidity and mortality, there are currently no licensed vaccines to prevent EBV infection or approved antiviral therapies that effectively treat EBV-associated diseases or eradicate latent infection.[2] Management of EBV-related conditions is largely supportive for acute illnesses like infectious mononucleosis, or involves complex oncological and immunological interventions for associated malignancies and autoimmune disorders. The absence of a prophylactic EBV vaccine represents a major unmet medical need globally.[14] An effective vaccine could potentially prevent infectious mononucleosis, reduce the incidence of EBV-associated cancers, and possibly mitigate the risk of developing MS and other autoimmune conditions linked to the virus. The growing understanding of EBV's role in MS, in particular, has provided a renewed impetus for vaccine development efforts.[2] Such a vaccine would have a profound public health impact by alleviating the burden of acute illness and potentially preventing severe long-term sequelae.

3. V350A: An Investigational EBV Vaccine Candidate

Overview of V350A and its Link to MDX2201

V350A is an investigational vaccine candidate currently under development for the prevention of diseases associated with Epstein-Barr Virus.[6] It is being evaluated in conjunction with another candidate, V350B, and a placebo in the ongoing Phase 1 clinical trial NCT06655324.[6] Both V350A and V350B are specific formulations or dose levels derived from the MDX2201 vaccine program, a nanoparticle-based vaccine candidate.[2] The "V" in V350A likely signifies "vaccine," and "350" may allude to the prominent EBV surface glycoprotein gp350, a key antigen in many EBV vaccine strategies. The suffixes "A" and "B" denote distinct investigational arms within the clinical trial, likely representing variations in antigen concentration, adjuvant use, or specific nanoparticle constructs, although precise details distinguishing V350A from V350B are not fully elucidated in the available information.[15]

Developers: Merck & Co., Inc. and ModeX Therapeutics (Opko Health)

The development of V350A is a collaborative effort. Merck Sharp & Dohme LLC (Merck) is the originator organization listed for V350A and the primary sponsor of the NCT06655324 clinical trial.[1] The underlying MDX2201 vaccine candidate and its platform technology were developed by ModeX Therapeutics, Inc., a clinical-stage biopharmaceutical company that is part of OPKO Health, Inc..[2]

Collaboration Framework and Significance

The partnership between Merck and ModeX Therapeutics was formalized through an exclusive worldwide license and collaboration agreement announced on March 8, 2023.[3] Under this agreement, ModeX granted Merck an exclusive, sublicensable, royalty-bearing license to certain patent rights and know-how related to the MDX2201 EBV vaccine candidate.[10]

This collaboration structure is common in the pharmaceutical industry, particularly for early-stage assets. It allows a larger, established pharmaceutical company like Merck, with extensive resources and experience in late-stage clinical development, regulatory affairs, and global commercialization, to access innovative technology from a smaller biotechnology company like ModeX. For ModeX, the collaboration provides significant non-dilutive funding, validation of its platform technology, and a pathway to bring a promising candidate to patients.

As part of the agreement, OPKO Health received an upfront payment of $50 million from Merck. Furthermore, OPKO is eligible to receive additional milestone payments totaling up to $872.5 million, contingent upon the achievement of specific development and commercialization milestones across various indications. The agreement also includes provisions for royalties on global sales of the vaccine, should it be successfully developed and commercialized.[10]

ModeX and Merck collaborated on advancing MDX2201 to the Investigational New Drug (IND) application filing with the U.S. Food and Drug Administration (FDA). Following IND acceptance, Merck assumed responsibility for leading all subsequent clinical development, regulatory activities, and potential future commercialization of the vaccine.[2] The initiation of the Phase 1 clinical trial (NCT06655324) triggered an undisclosed milestone payment from Merck to ModeX, as announced in January 2025.[2] This financial structure allows for shared risk and incentivizes both parties towards the successful progression of the vaccine candidate.

Table 1: Overview of the MDX2201/V350 EBV Vaccine Program

Feature	Description
Program Name	MDX2201 / V350 Program
Vaccine Candidates	V350A, V350B (specific formulations/doses of MDX2201)
Developers/Collaborators	ModeX Therapeutics (an OPKO Health company) and Merck & Co., Inc. (MSD)
Technology Platform	Ferritin nanoparticle vaccine platform displaying multiple recombinant EBV antigens 3
Target Antigens	Four EBV viral glycoproteins: gp350, gH, gL, and gp42 2
Intended Indication(s)	Prevention of EBV infection and associated diseases (e.g., infectious mononucleosis, EBV-related cancers, multiple sclerosis) 2
Current Development Phase	Phase 1 clinical trial (NCT06655324) 6

4. Scientific Rationale and Mechanism of Action

Vaccine Technology: Ferritin Nanoparticle Platform

The investigational EBV vaccine V350A, as part of the MDX2201 program, is based on ModeX Therapeutics' proprietary ferritin nanoparticle vaccine platform.[3] Ferritin is a naturally occurring iron storage protein that can self-assemble into a spherical, cage-like nanoparticle structure. This characteristic makes it an attractive scaffold for vaccine development. In this platform, recombinant EBV antigens are genetically fused to ferritin subunits. When these fusion proteins are expressed, they spontaneously assemble into nanoparticles that display multiple copies of the viral antigens on their surface in an organized, repetitive array.[3] The MDX2201 platform is designed to express as many as 24 copies of a recombinant antigen on the nanoparticle surface.[3]

This multivalent presentation of antigens mimics the repetitive patterns found on the surface of viruses and is intended to enhance immunogenicity. Such an organized display can lead to more efficient B cell receptor cross-linking and activation, potentially resulting in stronger and more durable antibody responses compared to traditional soluble protein antigens.[3] The use of bacterial ferritin has been mentioned in the context of this technology.[18]

Target Antigens: Multi-antigen approach

The V350A/MDX2201 vaccine employs a multi-antigen strategy, presenting components from four key EBV glycoproteins that are critical for viral entry into host cells:

• Glycoprotein 350 (gp350): The most abundant glycoprotein on the EBV virion surface, gp350 mediates the initial attachment of the virus to B cells by binding to the CD21 receptor (also known as CR2).[3] It has historically been a primary target for EBV vaccine development.
• Glycoprotein H (gH) / Glycoprotein L (gL) complex: The gH/gL complex is essential for the fusion of the viral envelope with the host cell membrane, a critical step for viral entry into both B cells and epithelial cells.[3]
• Glycoprotein 42 (gp42): This glycoprotein is crucial for EBV entry into B cells, as it interacts with human leukocyte antigen (HLA) class II molecules on the B cell surface to trigger membrane fusion, in conjunction with the gH/gL complex. It is less critical for epithelial cell entry, which often involves a gH/gL interaction with integrins.[3]

The MDX2201 vaccine candidate includes a recombinant antigen designed from the gH, gL, and gp42 proteins, as well as an antigen derived from gp350.[3] This approach contrasts with earlier EBV vaccine efforts that predominantly focused on gp350 alone, aiming for a more comprehensive immune blockade of viral entry mechanisms.[2]

Expected Immunological Response and Protective Mechanism

The primary goal of the V350A/MDX2201 vaccine is to elicit a robust and durable protective immune response, primarily characterized by the production of high-titer neutralizing antibodies against the four targeted EBV glycoproteins.[3] By presenting these antigens on a nanoparticle scaffold, the vaccine is designed to effectively stimulate the immune system to recognize these viral proteins as foreign and mount an efficient defense upon subsequent exposure to the live virus.[2]

The neutralizing antibodies generated are expected to block EBV infection through several mechanisms:

• Inhibition of B cell infection: Antibodies against gp350 can prevent viral attachment to CD21 on B cells. Antibodies against gp42 and the gH/gL complex can block the fusion process required for B cell entry.
• Inhibition of epithelial cell infection: Antibodies against the gH/gL complex can interfere with viral fusion with epithelial cells. While gp350 is less critical for epithelial cell entry, antibodies against it might still offer some level of protection or contribute to overall viral clearance.

By targeting these multiple essential viral proteins and their roles in infecting different cell types, the vaccine aims to provide broad protection against EBV infection and, consequently, reduce the incidence of EBV-associated diseases.[3] The enhanced presentation of antigens via the ferritin nanoparticle platform is anticipated to lead to superior immunogenicity compared to soluble protein approaches.[3]

5. Preclinical Development and Supporting Evidence

The development of the V350A/MDX2201 EBV vaccine candidate is underpinned by significant preclinical research, with key findings published in the May 2022 issue of Science Translational Medicine (PMID: 35507671).[3] This study, titled "A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice," by Wei, Bu, Nguyen, and colleagues, detailed the design and evaluation of a nanoparticle vaccine platform similar to that used for MDX2201.[19]

Summary of Key Preclinical Findings

The research described the construction of single-chain versions of EBV glycoproteins gH/gL and gH/gL/gp42. These engineered proteins were fused to bacterial ferritin, enabling their self-assembly into nanoparticles that display the viral antigens on their surface.[19] This design aimed to ensure product homogeneity, a critical factor for clinical development and manufacturing consistency.[19]

Immunogenicity and Efficacy in Animal Models

The preclinical studies demonstrated potent immunogenicity of these nanoparticle vaccines across multiple animal models:

• Neutralizing Antibody Induction: The vaccines successfully elicited high titers of neutralizing antibodies in mice, ferrets, and nonhuman primates.[19] These antibodies were shown to be functional, capable of inhibiting EBV entry into both B cells and epithelial cells in vitro, the two primary targets of EBV infection.[19]
• Bivalent Approach: When the gH/gL/gp42 nanoparticle vaccine was combined with a previously developed gp350 nanoparticle vaccine (designated gp350D123), no immune interference or competition between the antigens was observed. This supported the feasibility of a bivalent or multivalent vaccine formulation targeting multiple EBV entry proteins.[19]
• Protection in Humanized Mice: The protective efficacy of the bivalent vaccine approach (gH/gL/gp42 nanoparticles mixed with gp350D123 nanoparticles) was rigorously tested in a humanized mouse model. Humanized mice, which possess a reconstituted human immune system, allow for more relevant assessment of human-specific pathogens like EBV.
• In these challenge studies, mice received passive transfer of IgG (antibodies) purified from other mice that had been vaccinated with either the bivalent vaccine combination or a control preparation. Following antibody transfer, the mice were challenged with live EBV.
• The results were compelling: all control animals that received non-immune IgG became infected with EBV. In contrast, mice that received IgG from vaccinated animals showed near-complete protection against viremia (the presence of virus in the blood). Only one mouse in each of the vaccinated IgG recipient groups exhibited detectable, transient viremia.[19]
• Critically, the vaccine-induced antibodies also protected against EBV-associated pathology. No EBV-driven lymphomas, a common consequence of uncontrolled EBV infection in immunosuppressed or humanized mouse models, were detected in the animals that received immune IgG from the bivalent vaccine groups.[19]

These preclinical findings provided strong validation for the multi-antigen nanoparticle strategy. The ability to protect against both viral infection (viremia) and a significant EBV-associated disease (lymphoma) in a relevant animal model was a crucial step in demonstrating the vaccine's potential. The study concluded that this bivalent EBV nanoparticle vaccine represents a promising candidate for preventing EBV infection and its associated malignancies in humans.[19]

Safety Profile from Preclinical Studies

The abstracts and summaries of the Science Translational Medicine paper primarily focus on the immunogenicity and protective efficacy of the vaccine constructs.[19] While detailed toxicology data are not provided in these summaries, the successful protection observed in animal models without mention of significant adverse effects suggests a generally favorable preclinical safety profile. Formal safety and toxicology studies are a standard part of preclinical development before advancing to human trials.

The robust preclinical data, particularly the demonstration of protection against both infection and disease in humanized mice, formed a strong basis for advancing the MDX2201/V350 vaccine program into Phase 1 clinical trials.

6. Clinical Development Program: The V350-001 (NCT06655324) Trial

The V350A investigational EBV vaccine candidate, along with V350B, has progressed into early-stage human clinical trials. The cornerstone of this initial clinical evaluation is the V350-001 study.

Trial Identifier and Title

The trial is registered under the identifier NCT06655324. Its official title is "A Study to Evaluate Safety, Tolerability, and Immunogenicity of V350A and V350B in Healthy Participants (V350-001)".[6]

Study Objectives and Endpoints

The primary purpose of this Phase 1 trial is to assess the safety and tolerability of the V350A and V350B vaccine candidates in healthy adult volunteers.[6] While not explicitly stated as primary in all summaries, the evaluation of the immunogenicity of V350A and V350B is a key objective, as reflected in the trial's full title.[3]

• Primary Outcome Measures: These are expected to include standard safety assessments for vaccine trials, such as:
• The incidence and severity of solicited local adverse events (e.g., pain, redness, swelling at the injection site).
• The incidence and severity of solicited systemic adverse events (e.g., fever, fatigue, headache, myalgia).
• The incidence of unsolicited adverse events (AEs).
• The incidence of serious adverse events (SAEs).
• Results of safety laboratory tests. (Specific measures and timeframes are not fully detailed in the provided materials but are standard for Phase 1 vaccine studies).
• Secondary Outcome Measures: These will focus on the immune response elicited by the vaccines, likely including:
• Titers of EBV-specific neutralizing antibodies against the target antigens (gp350, gH/gL, gp42).
• Other immunological markers as deemed appropriate (e.g., binding antibody titers, T-cell responses). Immunogenicity is expected to be assessed at various time points over approximately 1.5 years.[2]

Trial Design

• Phase: Phase 1.[6]
• Design: The study is a randomized, placebo-controlled trial. Some sources describe it as double-blind [3], while others indicate triple-blind and utilizing sequential assignment.[15] It incorporates dose-escalation elements to evaluate different potential dose levels of the vaccine candidates.[3]
• Sponsor: Merck Sharp & Dohme LLC is the sponsor of the trial.[7]

Participant Population

• Number of Participants: The trial aims to enroll approximately 200 healthy adult participants.[2]
• Age Range: Eligible participants are aged 18 to 30 years, inclusive.[6]
• Key Inclusion Criteria: Participants must be in good health prior to randomization and have a Body Mass Index (BMI) between ≥18 and ≤35 kg/m2.[7]
• Key Exclusion Criteria: Individuals with a confirmed or suspected case of infectious mononucleosis within the 12 months preceding enrollment are excluded. Also excluded are those with any immunosuppressive medical condition or who are currently receiving immunosuppressive therapy.[7]

Intervention Arms

The trial includes three main intervention arms [7]:

• V350A: Participants assigned to this arm will receive vaccinations with the V350A candidate (Biological: V350A).[15]
• V350B: Participants assigned to this arm will receive vaccinations with the V350B candidate (Biological: V350B).[15] One source lists V350B as the primary treatment being investigated.[7]
• Placebo: Participants in this arm will receive placebo vaccinations (Biological: Placebo).[15]

The specific differences between the V350A and V350B vaccine formulations (e.g., antigen dosage, adjuvant composition, or variations in the nanoparticle construct) are not detailed in the provided information. This lack of clarity is a notable gap, as understanding these differences is crucial for interpreting the trial's dose-finding and formulation-selection objectives.

Dosage and Administration Route/Schedule

• Administration Route: The vaccines are administered via intramuscular injection.[2]
• Vaccination Schedule: Participants in all active and placebo arms will receive three injections, administered on Day 1, Month 2, and Month 6.[2]
• Dosage: Specific dosage levels for V350A and V350B are not provided in the available materials. As a dose-escalation trial, it is expected that different dose levels of V350A and/or V350B will be evaluated across different cohorts of participants.[3]

Current Recruitment Status, Timelines, and Study Locations

• Status: The trial is currently "Active - Recruiting" as of April 2025.[7] The first participant was dosed in early January 2025.[2]
• Actual Study Start Date: December 5, 2024.[6]
• Estimated Primary Completion Date: November 21, 2026.[6]
• Estimated Study Completion Date: November 21, 2026.[6]
• Study Locations: The trial is being conducted at multiple clinical research sites across the United States, including locations in California, Florida, Missouri, Nebraska, Oklahoma, and Tennessee.[6]

Table 2: Key Details of the NCT06655324 (V350-001) Phase 1 Clinical Trial

Feature	Detail
Trial Identifier	NCT06655324 (V350-001) 7
Official Title	A Study to Evaluate Safety, Tolerability, and Immunogenicity of V350A and V350B in Healthy Participants 7
Phase	1 7
Sponsor	Merck Sharp & Dohme LLC 7
Primary Objectives	To evaluate the safety and tolerability of V350A and V350B in healthy adults.6
Key Secondary Objectives	To evaluate the immunogenicity of V350A and V350B.3
Study Design	Randomized, Placebo-Controlled, Dose Escalation. Blinding described as Double-Blind or Triple-Blind. Sequential Assignment also mentioned.3
Number of Participants	Approximately 200.7
Target Population	Healthy adults, aged 18-30 years.6 Key criteria: good health, BMI 18-35 kg/m2; no recent mono, no immunosuppression.7
Intervention Arms	1. V350A (Biological: V350A) <br> 2. V350B (Biological: V350B) <br> 3. Placebo (Biological: Placebo) <br> (Specific differences between V350A and V350B, and dosages, are not detailed).15
Administration & Schedule	Intramuscular injections on Day 1, Month 2, and Month 6.2
Primary Outcome Measures	Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), local injection site reactions, systemic reactions. (Specific measures and timeframes not fully detailed but inferred from standard Phase 1 design).
Key Secondary Outcome Measures	EBV-specific neutralizing antibody titers against target antigens (gp350, gH/gL/gp42). Immunogenicity assessed over approximately 1.5 years. (Specific measures and timeframes not fully detailed but inferred).2
Actual Start Date	December 5, 2024.6
Estimated Primary Completion Date	November 21, 2026.6

This Phase 1 trial represents a critical initial step in the human testing of the V350A and V350B vaccine candidates. Its outcomes regarding safety, tolerability, and the nature of the immune response generated will be pivotal in guiding further clinical development of the MDX2201 EBV vaccine program. The lack of specific details differentiating V350A from V350B in the provided materials remains a key point of ambiguity at this stage.

7. Early Clinical Data (If Available) and Expected Safety/Tolerability Profile

Anticipated Safety and Tolerability

Based on the nature of the vaccine platform and general knowledge of vaccine safety, certain expectations can be formed regarding the safety and tolerability profile of V350A and V350B. Nanoparticle-based vaccines, including those utilizing ferritin as a scaffold, are generally designed to be well-tolerated. Common adverse events anticipated in a Phase 1 trial would typically include:

• Local Reactions: Pain, tenderness, redness, and swelling at the injection site are common, usually mild to moderate in severity, and transient.
• Systemic Reactions: Mild systemic symptoms such as fatigue, headache, myalgia (muscle pain), arthralgia (joint pain), and low-grade fever may occur, typically within a few days of vaccination and resolving spontaneously.

The ferritin platform itself is derived from a protein naturally found in biological systems (though bacterial ferritin is used here), which generally suggests a good biocompatibility profile.[18] The preclinical research supporting the MDX2201 platform, particularly the study published in Science Translational Medicine, reported successful immunogenicity and protection in animal models without highlighting significant safety concerns.[19]

Actual Phase 1 Data

The V350-001 (NCT06655324) clinical trial commenced with the dosing of its first participant in early January 2025.[2] Given this timeline and the typical duration required for data collection, analysis, and reporting in Phase 1 studies, no clinical data on the safety, tolerability, or immunogenicity of V350A or V350B from this human trial are available in the provided research materials, which generally have an information cut-off around mid-2025. The primary completion date for the trial is estimated to be November 21, 2026.[6] Therefore, any discussion of the actual human safety profile at this juncture would be speculative.

The absence of human clinical data is expected at this early stage of development. Phase 1 trials are specifically designed to gather this initial human safety and tolerability information, which will be crucial for decisions regarding continued development, dose selection for future trials, and the overall risk-benefit assessment of the vaccine candidates. Future development will also likely necessitate studies in younger age groups, particularly adolescents, who are a key demographic for symptomatic primary EBV infection (infectious mononucleosis). Data from the current trial in young adults might inform immunobridging strategies to extend the vaccine's use to these younger populations, a common approach in vaccine development, as seen with vaccines like the HPV vaccine.[20]

8. Intellectual Property and Regulatory Landscape

Relevant Patent Information

The intellectual property surrounding the V350A/MDX2201 EBV vaccine program appears to be multifaceted, involving rights originating from academic research, ModeX Therapeutics' proprietary platform, and licensing agreements with Merck.

ModeX Therapeutics has granted Merck an exclusive, worldwide, sublicensable, royalty-bearing license to certain patent rights and know-how pertinent to the EBV vaccine platform and the MDX2201 candidate.10 This agreement underpins Merck's leadership in the clinical development and potential commercialization of the vaccine.

A key patent application that seems highly relevant to the technology employed is WO2015054639A1, titled "Vaccines Comprising Nanoparticles that Display Epstein-Barr Virus (EBV) Envelope Proteins".[17] This patent application describes the core concept of using self-assembling proteins, such as ferritin, to create nanoparticles that display EBV envelope proteins—specifically citing gp350, gH, gL, and gp42 among others. This aligns directly with the described technology of the MDX2201 vaccine candidate, which utilizes a ferritin nanoparticle platform to present these same four EBV antigens.[3] While the inventors or original assignees listed in the snippet for WO2015054639A1 are not explicitly ModeX or Merck, the technological congruence strongly suggests its inclusion in the intellectual property portfolio licensed to Merck, possibly through ModeX's acquisition or in-licensing of foundational IP.

It is also noted that ModeX scientists have a background that includes work at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and Sanofi during the early development phases of this vaccine candidate technology.[16] Furthermore, certain rights subject to the license provided by ModeX to Merck were initially obtained by ModeX from Sanofi through a separate in-license agreement dated July 1, 2021.[10] This indicates a layered IP strategy, where foundational inventions may have originated from academic or governmental research institutions, further developed by biotechnology companies like Sanofi and then ModeX, and ultimately licensed to a major pharmaceutical company for late-stage development and commercialization.

Current Regulatory Status

V350A and V350B are investigational vaccine candidates. As of early 2025, they are in Phase 1 clinical development as part of the NCT06655324 trial.[6] The initiation of this Phase 1 trial signifies that Merck has received acceptance from the U.S. Food and Drug Administration (FDA) for its Investigational New Drug (IND) application, permitting human testing of these candidates.

No specific expedited regulatory designations, such as Fast Track, Breakthrough Therapy, or Priority Review from the FDA, or PRIME (PRIority MEdicines) designation from the European Medicines Agency (EMA), for V350A, V350B, or the MDX2201 program are mentioned in the provided documents.[24] Such designations are typically sought after initial positive clinical data emerge and if the candidate meets the criteria for addressing a serious condition with an unmet medical need. Given the early stage of development (Phase 1), applications for these designations may be planned for the future, contingent on favorable trial results. The successful progression through Phase 1, demonstrating an acceptable safety profile and promising immunogenicity, will be critical for subsequent discussions with regulatory authorities regarding the design of Phase 2 and Phase 3 trials and the potential for any accelerated development pathways.

9. Future Perspectives and Potential Impact

Potential of V350A in Preventing EBV-Associated Diseases

The successful development of V350A, as a derivative of the MDX2201 EBV vaccine program, holds substantial promise for global public health. If proven safe and effective, this vaccine could significantly reduce the incidence of acute infectious mononucleosis, a common and often debilitating illness in adolescents and young adults.[4] More profoundly, given the strong etiological links between EBV and various severe conditions, an effective prophylactic EBV vaccine could play a crucial role in preventing certain types of cancer, including nasopharyngeal carcinoma and various B cell and T cell lymphomas.[4] Furthermore, the compelling evidence associating EBV with an increased risk of multiple sclerosis suggests that an EBV vaccine might also contribute to reducing the incidence of this chronic neurological disease.[2] The potential market for a successful EBV vaccine is considerable, estimated to be in the range of $1.5-2 billion annually, reflecting the virus's ubiquity and the severity of its associated health burdens.[26]

Challenges and Next Steps in Development

Despite the promising technology and preclinical data, the path to a licensed EBV vaccine is fraught with challenges. Key next steps and hurdles include:

• Demonstrating Clinical Efficacy: Moving beyond Phase 1, the vaccine must demonstrate robust and durable immunogenicity and, critically, clinical efficacy in preventing EBV infection and/or disease in larger, more definitive Phase 2 and Phase 3 trials.
• Optimal Dosing and Schedule: The ongoing Phase 1 trial (NCT06655324) will provide initial data on safety and immunogenicity for V350A and V350B, which will inform the selection of the optimal dose and vaccination schedule for subsequent studies. The specific differences between V350A and V350B remain to be clarified and will be a key output of this early phase.
• Safety in Diverse Populations: Ensuring a favorable safety profile across diverse populations, including different age groups (particularly adolescents, a primary target for mononucleosis prevention) and individuals with varying genetic backgrounds, will be essential.
• Manufacturing and Scale-Up: The production of nanoparticle-based vaccines can be complex. Establishing a robust, scalable, and cost-effective manufacturing process will be critical for widespread availability.
• Long-Term Protection: Determining the duration of protective immunity and whether booster doses will be required are important long-term considerations.

Broader Context of EBV Vaccine Research

The V350A/MDX2201 program is part of a renewed global effort in EBV vaccine research. Its multi-antigen, nanoparticle-based platform aligns with modern vaccine design principles that aim to elicit broader and more potent immune responses compared to earlier, simpler approaches.[3] The field is also exploring other technologies, such as mRNA vaccines and viral vector-based vaccines, for EBV. The progress of the V350A program will be closely watched and benchmarked against these other efforts. Success in this program could further validate the utility of ferritin nanoparticle platforms and multi-component antigen strategies for other complex viral pathogens.

The development timeline for vaccines is typically lengthy, often spanning 5-7 years or more from Phase 1 to potential approval, even with accelerated progress.[26] With the Phase 1 trial for V350A estimated to complete its primary phase in late 2026 [6], a licensed vaccine, if successful, is still several years away.

10. Conclusion and Expert Analysis

The investigational vaccine candidate V350A, developed under the MDX2201 Epstein-Barr Virus (EBV) program through a collaboration between Merck Sharp & Dohme LLC and ModeX Therapeutics (an Opko Health company), represents a significant and scientifically advanced effort to address a long-standing unmet medical need. The vaccine leverages a sophisticated ferritin nanoparticle platform designed to present multiple key EBV antigens (gp350, gH, gL, and gp42) to the immune system. This multi-target strategy aims to elicit a comprehensive neutralizing antibody response capable of preventing EBV infection of its primary cellular targets, B cells and epithelial cells. The initiation of the Phase 1 clinical trial, NCT06655324, evaluating V350A alongside V350B, is a critical milestone in assessing the safety, tolerability, and immunogenicity of these candidates in healthy human adults.

The scientific rationale underpinning the V350A/MDX2201 program is robust. The multi-antigen approach directly addresses the complex nature of EBV entry and is a logical progression from earlier vaccine strategies that often focused more narrowly, primarily on gp350. The ferritin nanoparticle technology offers a promising means of enhancing antigen presentation and immunogenicity. Preclinical studies, particularly the findings published in Science Translational Medicine (May 2022), provide compelling evidence from animal models, including humanized mice, demonstrating the vaccine platform's ability to induce potent neutralizing antibodies and confer protection against both EBV viremia and EBV-associated lymphoma. This level of preclinical validation is a strong positive indicator.

However, the journey from a promising preclinical candidate to a licensed vaccine is long and complex. The immediate challenge lies in the outcomes of the ongoing Phase 1 trial. Clear demonstration of an acceptable safety profile and robust, broad neutralizing antibody responses against all targeted EBV antigens in humans will be paramount for Merck and ModeX to proceed with confidence into more extensive and costly Phase 2 and Phase 3 efficacy trials. A significant current limitation in the available public information is the lack of specific details distinguishing the V350A and V350B candidates being tested in NCT06655324. Understanding the differences in their formulation or dosage is key to interpreting the trial's objectives and eventual results concerning candidate selection and optimization.

Looking ahead, should V350A or a related candidate from this program prove successful, the public health impact would be substantial. An effective EBV vaccine could drastically reduce the burden of infectious mononucleosis and, more importantly, holds the potential to decrease the incidence of several EBV-associated malignancies and potentially lower the risk of developing multiple sclerosis. The V350A/MDX2201 program will be closely monitored within the scientific and medical communities, as its progress will not only determine the fate of this specific candidate but also provide valuable insights into the viability of advanced nanoparticle vaccine platforms for other challenging viral targets. The path forward requires rigorous clinical evaluation, addressing manufacturing complexities, and ensuring long-term safety and efficacy across diverse populations.

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