RPP5 Antibody

What is the primary objective of BARDA's RPP for COVID-19 monoclonal antibody therapeutics?

The primary objective is to develop COVID-19 monoclonal antibody therapeutics (either single or combination products) specifically for pre-exposure prophylaxis (PrEP) through FDA licensure. These therapeutics aim to provide rapid pre-exposure protection against SARS-CoV-2 infection, particularly for special populations such as adults and pediatrics who are moderately to severely immunocompromised and may not mount adequate immune responses to COVID-19 vaccines, or for whom vaccination is not recommended .

What variants must candidate monoclonal antibodies demonstrate activity against?

Candidate monoclonal antibodies must demonstrate in vitro activity against currently known variants of SARS-CoV-2 designated by WHO or CDC as Variants of Concern (VOC) or Variants Being Monitored (VBM). The comprehensive list includes:

Note: The F456L mutations are found in many lineages including EG.5, FL.1.51, and XBB.1.16.6 .

What potency requirements must candidate monoclonal antibodies meet?

For SARS-CoV-2, in vitro potency must be in the nanomolar range. Data must be generated from qualified and/or validated live virus and/or pseudo-virus neutralization assays. Additionally, candidates should demonstrate sufficient potency to support intramuscular and/or subcutaneous administration with no more than two injections once every six months .

What technology readiness level (TRL) is preferred for candidate submissions?

BARDA prefers candidates at a technology readiness level (TRL) of 6 or later, though earlier stage candidates may be considered. This indicates a preference for candidates that have already demonstrated efficacy in a relevant environment and are approaching system prototype demonstration in an operational environment .

What are the eligibility criteria for researchers to apply for this RPP?

Researchers must meet two key eligibility criteria:

• Offerors must be RRPV (Rapid Response Partnership Vehicle) members when the proposal is submitted

• Demonstrable successful history of developing, cGMP manufacturing, release testing, and conducting clinical trials for therapeutics and/or vaccines

How should researchers approach epitope mapping to demonstrate a high barrier to resistance?

Researchers must provide comprehensive epitope mapping data that demonstrates their monoclonal antibody product has a high barrier to resistance. This should include evidence that multiple mutations are required to generate a resistance variant that is as fit as other circulating variants. The methodology should involve:

• Systematic mapping of binding epitopes on the SARS-CoV-2 spike protein

• Identification of critical residues for antibody binding

• Evaluation of natural variant sequences at these positions

• Fitness cost analysis of potential escape mutations

• For combination products, demonstration that escape from multiple antibodies requires multiple independent mutations

What methodologies are recommended for enhancing antibody half-life?

Researchers must provide a clear approach for achieving extended half-life for candidate monoclonal antibodies, with supporting data demonstrating the typical half-life for antibodies with the planned modification. Methodological approaches may include:

• Fc engineering to enhance neonatal Fc receptor (FcRn) binding

• Amino acid substitutions at key positions in the Fc region

• Glycoengineering to optimize antibody stability

• Novel formulation strategies to reduce degradation

• Fusion proteins or other molecular modifications

The data should support a half-life sufficient to maintain protective levels with administration once every six months or longer .

What cross-reactivity studies are given preferential consideration?

Proposals demonstrating in vitro potency against not only SARS-CoV-2 but also MERS-CoV and SARS-CoV are given preferential consideration. Researchers should design studies that:

• Use standardized neutralization assays across all three coronaviruses

• Target conserved epitopes across betacoronaviruses

• Evaluate binding affinity and neutralization potency

• Assess cross-protective potential in appropriate animal models

• Define the structural basis for cross-reactivity through crystallography or cryo-EM studies

How should a regulatory strategy be structured for COVID-19 monoclonal antibodies?

Researchers must develop and implement a regulatory strategy and clinical development plan for obtaining FDA licensure, using aggressive risk management and taking advantage of any regulatory flexibilities. The strategy should:

• Include potential application for Emergency Use Authorization (EUA)

• Define clear development milestones aligned with regulatory requirements

• Incorporate early and frequent engagement with the FDA

• Anticipate and address potential regulatory challenges

• Include mechanisms to facilitate cross-referencing of regulatory files (INDs, Master Files, BLAs)

• Accommodate both standard approval pathways and emergency use provisions

What manufacturing considerations are preferred for monoclonal antibody candidates?

Manufacturing preferences include:

• Manufacturing in a cGMP-compliant facility in the United States

• Demonstrated manufacturing process capable of supporting clinical trials at the time of proposal submission

• Potential for scaling production to meet public health needs

• Quality control processes that ensure consistent product quality

• Consideration of novel manufacturing platforms that may enhance speed or reduce costs

What elements are essential in a non-clinical development plan?

Researchers must develop and implement a non-clinical development plan that includes:

• IND-enabling studies (toxicology/ADME)

• In vivo efficacy studies in appropriate animal models

• Tissue cross-reactivity studies

• Pharmacokinetic/pharmacodynamic (PK/PD) analyses

• Immunogenicity assessments

If in vivo efficacy studies or tissue cross-reactivity studies have not yet been completed, researchers must develop and implement a plan to complete these activities within six months after project award .

How should clinical trials be designed for monoclonal antibodies intended for PrEP?

Researchers must conduct phase-appropriate clinical trials following Good Clinical Practice (GCP) guidelines to support product registration and licensure by the FDA. The clinical development plan should:

• Include phase 1, phase 2, and pivotal phase 3 trials as necessary

• Focus on immunocompromised populations who cannot mount adequate responses to vaccines

• Define appropriate endpoints that demonstrate protection from SARS-CoV-2 infection

• Include pharmacokinetic studies to support dosing regimens

• Evaluate both safety and efficacy in the intended populations

• Consider ethical aspects of trial design, particularly for vulnerable populations

What assay validation criteria should be used for testing neutralization against SARS-CoV-2 variants?

For in vitro potency testing, researchers must use qualified and/or validated live virus and/or pseudo-virus neutralization assays. Methodological considerations include:

• Assay qualification/validation parameters (specificity, precision, accuracy, range)

• Use of appropriate reference standards

• Inclusion of relevant SARS-CoV-2 variants as specified in the RPP

• Correlation of neutralization titers with protection

• Standardized reporting of neutralization data (IC50, IC90 values)

How should project management be structured to meet BARDA requirements?

The project agreement holder (PAH) must implement a structured project management approach that includes:

• Regular, recurring progress meetings with the Government

• Submission of meeting agendas in advance and minutes following meetings

• Monthly technical and financial reports, including a master schedule

• Annual reports and, at the end of the effort, a detailed clinical study report

• A final technical and business report

• Management of all intellectual property, material, and sample shipments

• Maintenance of all associated records and permits

What are the cost-sharing expectations for research proposals?

While cost sharing is not required to be eligible for an award, the Government anticipates a minimum 30% cost-sharing agreement for this effort. Researchers should clearly state:

• The amount being proposed for cost sharing

• Whether the cost sharing is a cash contribution or an in-kind contribution

• Description of each cost share item proposed

• The proposed dollar amount for each cost share item

• The valuation technique used (e.g., vendor quote, historical cost, labor hours and labor rates, number of trips, etc.)

What is the anticipated period of performance for awarded projects?

The anticipated Period of Performance for this effort is up to seven (7) years from the date of award for design, manufacturing, non-clinical testing, and clinical trials performed only in the United States. Specific dates of performance will be negotiated as part of each offeror's submission .

How should researchers handle regulatory submissions and interactions?

Researchers must:

• Serve as regulatory product sponsor and be responsible for all regulatory submissions to the FDA

• Support and maintain regulatory submissions throughout the life of the project

• Submit to the Government all regulatory and supporting documentation related to therapeutic development

• Cross-reference applicable regulatory files prior to conducting studies

• Allow cross-referencing of documents associated with this effort

• Ensure all non-clinical and clinical studies are approved in accordance with industry standards and HHS requirements

What optional tasks may researchers propose to enhance their submissions?

To further support BARDA's mission to prepare and respond rapidly to emerging viral threats, researchers may propose optional tasks to:

• Advance cost-effective, quickly adaptable alternative manufacturing platforms for antibody therapeutics

• Expand the scope to address additional coronaviruses or variants

• Develop innovative delivery mechanisms

• Explore combination approaches with other therapeutic modalities

• Investigate novel stability or formulation approaches

How does BARDA evaluate in vitro potency against SARS-CoV-2 variants?

BARDA requires in vitro potency in the nanomolar range against currently known variants. Methodological considerations for researchers include:

• Using qualified and/or validated live virus neutralization assays

• Using qualified and/or validated pseudo-virus neutralization assays

• Testing against comprehensive panels of variants as specified in the RPP

• Standardizing assay conditions across variant testing

• Providing comparative analysis across variant susceptibility

What are the place of performance requirements for awarded projects?

• Location of manufacturing facilities (preferably U.S.-based)

• Clinical trial site selection within the United States

• Laboratory testing capabilities

• Regulatory expertise and location

• Project management coordination