Amendment_1_-_Research_Area_003_-_Collaborative_Influenza_Vaccine_Innovation_Centers_(CIVICs).pdf

AMENDMENT OF SOLICITATION

Solicitation Number: HHS-NIH-NIAID-BAA2018 Amendment Number: 1

AMENDMENT ONE (1)

Issued by:

National Institute of Allergy and Infectious Diseases (NIAID) Office of Acquisitions 5601 Fishers Lane, 3rd Floor Bethesda, MD 20892

Solicitation Number:

HHS-NIH-NIAID-BAA2018

Date of Solicitation Issuance: Date of Amendment No. 1 Issuance:

06/01/2018 07/03/2018

Number of Pages: Attachments:

31 Pages HHS-NIH-NIAID-BAA2018 – Amendment 1

Amendment Point of Contact: Research Area 003 Point of Contact:

George Kennedy Michael Finn Email: kennedyg@mail.nih.gov Email: finnm@niaid.nih.gov Phone: 240-669-5170 Phone: 240-669-5125

Offerors MUST acknowledge receipt of the amendment by Amendment number(s) and date of the amendment.

FAILURE OF YOUR ACKNOWLEDEMENT TO BE RECEIVED AT THE PLACE

DESIGNATED FOR THE RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE

SPECIFIED MAY RESULT IN REJECTION OF YOUR OFFER.

Except as provided herein, all terms and conditions of the solicitation remain unchanged and in full force and effect.

mailto:kennedyg@mail.nih.gov mailto:finnm@niaid.nih.gov

Purpose of Amendment 1:

The purpose of Amendment 1 is twofold:

1. To add RESEARCH AREA 003, “Collaborative Influenza Vaccine Innovation Centers

(CIVICs)” to the 2018 Omnibus Broad Agency Announcement:

RESEARCH

AREA

NIAID

DIVISION TITLE

RECEIPT

DATE AND

TIME:

003 DMID/DAIT Collaborative Influenza Vaccine Innovation Centers (CIVICs)

11/29/2018 *

* Proposals must be received before 3:00 PM Eastern Time on the date specified herein.

Please see the Proposal Submission Instructions for more information.

Offers will be valid for 240 days unless a different period is specified by the Offeror on the Attachment entitled, "Proposal Summary and Data Record, NIH 2043.

2. To provide the revised solicitation: “HHS-NIH-NIAID-BAA2018 – Amendment One”, attached hereto, incorporating the revision identified above.

Accordingly, SECTIONS 2 and 3 of the solicitation are revised as follows:

SECTION 2. - CONTRACTING OFFICER POINTS OF CONTACT, is revised as follows:

SECTION 2. - CONTRACTING OFFICER POINTS OF CONTACT

This BAA contains Research Areas issued by the Division of Microbiology and Infectious Diseases (DMID) within the National Institute of Allergy and Infectious Diseases. The Contracting Officer point of contact for questions related to specific Research Areas issued by the Division of Microbiology and Infectious Diseases (DMID) is identified below:

Division of Microbiology and Infectious Diseases (DMID)

Research Area 001: Development of Therapeutic Products for Biodefense, Anti-Microbial Resistant (AMR) Infections and Emerging Infectious Diseases

Research Area 002: Advanced Development of Vaccine Candidates for Biodefense and

Emerging Infectious Diseases

George Kennedy, J.D.

Contracting Officer

Phone: (240) 669-5170 Email: kennedyg@mail.nih.gov

Division of Microbiology and Infectious Diseases (DMID) and Division of Allergy, Immunology, and Transplantation (DAIT)

Research Area 003: Collaborative Influenza Vaccine Innovation Centers (CIVICs)

Michael C. Finn, M.B.A.

Contracting Officer Phone: (240) 669-5125 Email: finnm@niaid.nih.gov

SECTION 3. – RESEARCH AREAS AND TECHNICAL OBJECTIVES, is revised to add SECTION

3.2 – DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID), NIAID and DIVISION OF ALLERGY, IMMUNOLOGY, AND TRANSPLANTATION (DAIT), NIAID, as follows:

SECTION 3. - RESEARCH AREAS AND TECHNICAL OBJECTIVES

3.2 - DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID), NIAID and

DIVISION OF ALLERGY, IMMUNOLOGY, AND TRANSPLANTATION (DAIT),

NIAID

3.2.1 - BACKGROUND

Research supported by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), strives to understand, treat and ultimately prevent the myriad infectious, immunologic and allergic diseases that threaten millions of human lives.

NIAID supports a robust program in basic immunology that includes detailed analyses of human immune responses to pathogenic infections and/or vaccines.

NIAID also has a key role in the development and evaluation of medical countermeasures (MCMs) against potential agents of bioterrorism, drug-resistant pathogens and emerging and re-emerging infectious diseases, including seasonal and pandemic influenza.

Influenza is an acute viral infection caused by the influenza virus that results in pandemics and seasonal epidemics. Seasonal influenza epidemics result in 3-5 million severe cases and 290,000-650,000 deaths globally each year. Influenza pandemics emerge at unpredictable intervals and cause significantly increased morbidity and mortality than seasonal influenza epidemics. The cornerstone of influenza prevention and control is strain-specific vaccination. The remarkable capacity of influenza viruses to undergo antigenic drift or shift and evade pre-existing immunity necessitates annual development and administration of vaccines to protect against seasonal influenza. Current design methods for seasonal influenza vaccines rely primarily on the identification and matching of circulating viral strains with the vaccine strains. This approach contributes to vaccine efficacies that range mailto:kennedyg@mail.nih.gov mailto:finnm@niaid.nih.gov from 10-60%. Improved seasonal vaccines and more broadly and durably protective universal influenza vaccines are needed to limit the public health consequences of seasonal and pandemic influenza. Significant improvements in seasonal influenza vaccine efficacy and the development of universal influenza vaccines relies on a deeper understanding of the mechanisms required to induce protective immunity and better integration of this into vaccine design. Advances in the areas of human immunology, influenza virology, vaccinology, structural biology, next-generation genomic sequencing and emerging technologies will make the development of a universal influenza vaccine more feasible than it was a decade ago.

NIAID developed a Universal Influenza Vaccine Strategic Plan that describes three research areas paramount to advancement towards a universal influenza vaccine (EJ Erbelding et al. A universal influenza vaccine: The strategic plan for the National Institute of Allergy and Infectious Diseases. Journal of Infectious Diseases, 2018).

The three research areas include: natural history, pathogenesis and transmission studies utilizing prospective cohorts; studies to improve our understanding of influenza immunity and correlates of immune protection; and development and evaluation of next generation vaccines utilizing rational design strategies to elicit broad, protective immune responses. The critical research activities needed to achieve such a goal were identified during the “Pathway to a Universal Influenza Vaccine” workshop held June 28–29, 2017, which brought together a diverse group of U.S. and international scientists and clinicians from industry, academia and government.

Through this BAA, NIAID aims to advance research and development of promising new influenza vaccines that provide broader protection and immunity and that will last for a longer period than what is currently afforded, by supporting a coordinated multi-disciplinary effort of guided discovery, facilitated product development and managed progress through iterative testing in pre-clinical studies, clinical trials and human challenge studies.

The Collaborative Influenza Vaccine Innovation Centers (CIVICs) will be composed of the following components:

Research Area 003: Component A: Vaccine Center Research Area 003: Component B: Vaccine Manufacturing and Toxicology Core Research Area 003: Component C: Clinical Core

Summary of scenarios for proposal submission: Proposals may be submitted as follows:

1. Component A alone: Vaccine Center with all required activities (i.e., Leadership and Project Management; Vaccine Design and Development; Immunologic Analyses; and Assay and Reagent Core) https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiy103/4904047

3.2.2.1 - Research Area 003 – Collaborative Influenza Vaccine Innovation Centers (CIVICs)

2. Component B alone: Vaccine Manufacturing and Toxicology Core with all required activities (i.e., Vaccine Manufacturing, Formulation and Delivery; and GLP Toxicology)

3. Component C alone: Clinical Core with all required activities (i.e., clinical trials, human challenge studies and human sample repository)

Or

4. Offerors may submit proposals for one or more of the above components, however, each component should be submitted as a separate proposal

The NIAID reserves the right to award all or any portion of the projects/activities proposed based on technical merit, importance to agency programs and the availability of funds.

3.2.2 - RESEARCH AREAS

3.2.2.1.1 - Budget and Award Information

NIAID estimates that two or more awards may be issued for Research Area 003 Component A for a total first year base cost (direct and indirect costs combined) of roughly $13 million each; one award may be issued for Research Area 003 Component B for a total first year base cost of roughly $500,000; and one award may be issued for Research Area 003 Component C for a total first year base cost of roughly $1 million, depending on the number of technically meritorious proposals, importance to agency programs, and availability of funds. The total cost for each award(s) may vary depending upon the scope of the project and the technical objectives of the award(s).

The total duration of a proposed contract should be consistent with the nature and complexity of the offeror’s proposed research. The total performance period comprised of the base and any options proposed by an Offeror should not exceed seven (7) years.

Awards are anticipated to be made in or around August 2019.

3.2.2.1.2 - Technical Objectives

The objective of Research Area 003 is to support improvements in the immunogenicity and durability of seasonal influenza vaccines, and the development of innovative influenza vaccine approaches that provide robust, durable, broadly protective mucosal and systemic anti-influenza immunity (“universal influenza vaccines”). Research Area 003 will support iterative vaccine design based on detailed immunologic assessment of influenza vaccine candidates through pre-clinical animal studies, early phase clinical trials and healthy volunteer human challenge studies to advance the most promising vaccine candidates into Phase I/II clinical trials.

The desired attributes of a universal influenza vaccine are that it:

• Be at least 75% effective against symptomatic influenza virus infection.

• Protect against group I and group II influenza A viruses (influenza B virus would be a secondary target).

• Provide durable protection that lasts at least one year and preferably through multiple influenza seasons.

• Be suitable for all age groups, recognizing that different vaccines may be needed to provide optimal protection in certain populations.

NIAID will work with the Contractors to facilitate a CIVICs program that:

• Is comprised of well-integrated, multi-disciplinary teams of investigators that work collaboratively across Centers and Cores to support the research objectives of this program as guided by NIAID.

• Employs state-of-the-art, cutting-edge techniques and strategies, and bring in expertise from outside of the influenza field, to design innovative influenza vaccine approaches.

• Employs an iterative process, based on principles of influenza immunity, to achieve the desired attributes of a universal influenza vaccine.

• Works collaboratively to test novel combinations and conduct head-to-head comparisons of influenza vaccine approaches under development in order to identify, down-select and advance the most promising vaccine candidates.

• Collaborates with and leverage other NIAID extramural and intramural research programs to contribute to the development of universal and improved seasonal influenza vaccines.

3.2.2.1.3 - Technical Approach

3.2.2.1.3.1 - Research Area 003 Component A: Vaccine Center

The objective of Research Area 003 Component A is to design and evaluate innovative influenza vaccine approaches, based on principles of influenza immunity, that achieve durable, robust and broadly protective immunity. Requirements include iterative vaccine design and development; immunologic analyses to inform vaccine design and identify surrogates/correlates of protection including in vitro and in vivo immunogenicity and efficacy testing; and assay and reagent development.

Component A is composed of the following activities: Leadership and Project Management; Vaccine Design and Development; and Immunologic Analyses, as well as an Assay and Reagent Core. These activities shall be well-integrated and work together collaboratively to achieve the objectives outlined below.

1. Leadership and Project Management

• Implement a Scientific Leadership Group (SLG) that will be responsible for the execution of research and be minimally comprised of the scientific leads for Vaccine Design and Development and Immunologic Analyses and 1-2 other leading investigators from the Center.

• Manage, coordinate and oversee the Vaccine Center’s activities; monitor progress; and ensure the effective and efficient implementation and conduct of all proposed activities including, but not limited to:

• Reallocate resources in support of changing research and vaccine design and development needs.

• Develop and implement metrics and milestones to monitor, quantify and evaluate progress and productivity.

• Make recommendations for collaborations with existing internal and external programs (NIAID-supported and beyond).

• Develop and implement a plan delineating the processes and approaches to establish priorities; develop and review new research activities;

identify and select immunogen/vaccine constructs for current Good Manufacturing Practice (cGMP) manufacturing and clinical studies; and discontinue support of unproductive or unneeded research activities.

Plan shall include discussion of the coordination of activities across the CIVICs program and consultation with an External Advisory Group.

• Prepare and provide technology transfer plans, as appropriate, for vaccines and other technologies used or developed by the Vaccine Center.

• Develop and manage a pilot and cross-center research program to support innovative research projects, including cross-Center collaborations, with the potential for high impact on understanding influenza immunity and furthering influenza vaccine development.

• Develop and implement Quality Assurance/Quality Control (QA/QC) processes and a reporting structure for evaluation of products, reagents and assays utilized by the Vaccine Center whether developed internally or procured from other sources.

• Develop a plan for the management of experimental and processed data and reagents generated by the Vaccine Center to ensure tracking and export of data to the CIVICs Statistical, Data Management and Coordination Center (SDMCC) and deposition of reagents to repositories designated by NIAID.

• Ensure that samples, reagents, protocols and data generated by the Vaccine Center are shared with the broader scientific community in accordance with NIH policies, in collaboration with the independent CIVICs Clinical Core and SDMCC.

• Develop plans for collaboration, harmonization, leveraging of shared resources, centralization of laboratory activities and data sharing in the event that more than one Vaccine Center is awarded.

2. Vaccine Design and Development

• Rationally design innovative influenza vaccine immunogens, antigen/adjuvant combinations, and delivery platforms that provide robust, durable, broadly protective mucosal and systemic immunity, with:

• Emphasis on multi-valent and cross-protective vaccine strategies for healthy adults and populations at-risk for severe disease (e.g., infants, young children, pregnant women, elderly, immunocompromised individuals), recognizing that different vaccines may be needed to provide optimal protection in certain populations.

• Incorporation of novel adjuvants such as those from industry or NIAID’s adjuvant discovery and development programs.

• Incorporation of structural biology and computational modeling to inform antigen design and adjuvant-antigen sparing.

• Exploration of sequential and combinatorial approaches, and alternate routes of delivery and immunization schedules.

• Explore improvements to seasonal influenza vaccines to improve immunogenicity and durability for all age groups.

• Conduct pre-clinical immunological analyses of influenza vaccine candidates (see Immunological Analyses section below) to inform vaccine design and select the most promising vaccine candidates for further development.

• Conduct pre-clinical evaluation of at least three unique vaccine candidate/platforms that are anticipated to induce broadly protective, durable immunity.

• Candidate vaccines/platforms may be at varying stages of pre-clinical or early clinical (Phase I) development and the studies proposed should align with the stage of development.

• Novel antigens, antigen/adjuvant combinations and platforms that target multiple arms of the immune system are encouraged.

• Conduct pre-clinical evaluation of multiple vaccine approaches and platforms in combination and head-to-head comparisons, including those developed through CIVICs and from other NIAID or externally-supported programs.

• Work collaboratively with the CIVICs Clinical Core and SDMCC to design and implement ethical and statistically sound clinical trials and human challenge studies of promising vaccine candidates.

• Refine and optimize vaccine approaches based on data from pre-clinical studies, clinical trials and human challenge studies.

• Work collaboratively with the CIVICs SDMCC to ensure timely submission of data to the SDMCC for internal management and submission to publicly accessible repositories designated by NIAID.

3. Immunologic Analyses

• Conduct iterative, pre-clinical, immunological characterization of systemic and mucosal immune responses to universal and improved seasonal influenza vaccine candidates to inform vaccine design and select the most promising vaccine candidates for further development. Activities shall include:

• Design and implementation of detailed systems immunology evaluation of vaccine candidates in appropriate animal models. Immunologic analyses shall minimally include:

o Quantitative and qualitative/functional evaluation of innate immune cell, B cell and T cell responses in blood and relevant tissues/mucosal sites (e.g., draining lymph nodes, lung, upper airways) to the vaccine candidates.

o Determination of the isotype, magnitude and quality/function of vaccine-specific antibodies in blood, tissues and airway secretions.

o Characterization of immunologically relevant cells, metabolites, cytokines and other soluble mediators in blood, tissues and airway secretions to facilitate the identification of immune correlates in blood or other easily accessible body fluids/tissues that may serve as indicators of systemic and/or tissue-specific protective immunity.

o Assessment of the impact of pre-existing immunity and sequential/repeat vaccination on vaccine immunogenicity and efficacy using appropriate animal models, which may be coupled with computational analyses.

• Design and/or implementation of in vitro human immune cell cultures (e.g., lymphocyte proliferation/function assays, artificial human immune systems) or ex vivo human organoid systems for detailed preliminary evaluation of human innate and adaptive immune responses, including existence of vaccine-specific T cell and B cell specificities in the pre-immune/immune antigen receptor repertoires and qualitative analyses of antibody function.

• Use advanced analytical bioinformatics tools and/or computational modeling approaches to analyze and integrate immunologic data, and other data types generated or collected as phenotypic data in animals and human culture systems, to facilitate selection of the most promising vaccine candidates for clinical evaluation.

• Conduct comprehensive immunological studies of human systemic and mucosal immune responses to influenza vaccine candidates from clinical trials and human challenge studies. Longitudinal analyses shall be conducted for a minimum of one year post-vaccination or challenge.

Studies shall minimally include characterization of immunologically relevant cells, metabolites, cytokines, antibodies and other soluble mediators in blood, tissues and airway secretions pre- and post-vaccination and/or challenge, including:

• Evaluation of antigen receptor repertoires to identify associations between clonotypic B and T cells responses and reduction/prevention of clinical disease (or exacerbation of infection, if applicable).

• Evaluation of B cell subsets, including memory B cell subsets, antibody secreting cells, and long-lived plasma cells.

• Evaluation of T cell subsets, including memory T cell subsets, T follicular helper cells, regulatory T cells and cytotoxic T lymphocytes.

• Evaluation of neutralization by vaccine-specific antibodies (e.g., hemagglutination inhibition (HAI), microneutralization (MN), neuraminidase inhibition (NI)).

• Evaluation of Fc-dependent, antibody-mediated protection (e.g., antibody-dependent cellular cytotoxicity, opsonophagocytosis).

• Determination of the roles of innate cells (e.g., NK cells, dendritic cells, monocytes, alveolar macrophages) and their subsets in protection, especially where innate cells may serve as effector cells for antibody-mediated cytotoxicity, phagocytosis or inflammatory processes.

• Assessment of the impact of pre-existing immunity and sequential/repeat vaccination on vaccine efficacy and long-lived immunity.

• Identify surrogates of long-lived immune protection at earlier time points following vaccination. Examples include:

• Analysis of cytokines, metabolites and other soluble mediators in serum or other clinical samples predictive of long-term protection.

• Surface markers on lymphocytes that indicate commitment to long-lived lymphocyte compartments, which may include memory cells, tissue resident effector memory cells and the bone marrow-resident, long-lived plasma cell compartment.

• Transcription factors, signaling pathways, metabolites and other intracellular pathways indicative of commitment of lymphocytes to long-lived lymphocyte compartments, which may include memory cells, tissue resident effector memory and the bone marrow-resident long-lived plasma cell compartment.

• Work collaboratively with the CIVICs Clinical Core and SDMCC in the design of all clinical trials and human challenge studies to ensure:

• Appropriate collection, processing and storage of human samples for detailed immunologic analyses. This activity includes selection of appropriate test populations, time points and samples (blood, draining lymph nodes, nasal secretions, bronchoalveolar lavage, tissues, etc.) for analyses of innate and adaptive immune cells and metabolites pre-vaccination and for a minimum of one year post-vaccination, to determine durability and broad immune protection.

• Inclusion of adequate subjects to detect statistically significant differences in immunity to vaccine candidates (e.g., power analyses and statistical sensitivity).

• Work collaboratively with the CIVICs SDMCC to ensure timely submission of data to the SDMCC for internal management and submission to publicly accessible repositories designated by NIAID.

4. Assay and Reagent Core

• Design, develop, qualify and validate protocols, reagents and assays for in vitro and in vivo pre-clinical and clinical characterization and evaluation of influenza vaccine immunogenicity and efficacy, in compliance with applicable Good Laboratory Practice (GLP) and cGMP regulations, with an emphasis on high-throughput assays for measuring immunity (innate and/or adaptive) against multiple influenza virus strains. Activities include:

• Develop, produce, procure and/or characterize assay reagents and required components.

• Develop vaccine-specific reagents and assays for the most promising vaccine candidates that will be transitioned to Phase I/II clinical trials through the Clinical Core.

• Conduct method assessment/feasibility studies and method comparability studies.

• Technology transfer of assays and reagents to and from other CIVIC Vaccine Centers.

• Establish synergistic, collaborative relationships that foster centralization of protocols, reagents and assays across the entire CIVICs program to take advantage of particular expertise within a CIVICs Center or Core, provide a key service/technology and/or eliminate duplication of effort.

• Work collaboratively with the CIVICs SDMCC to prepare documentation for pre-clinical assay development, qualification, validation and regulatory submissions.

3.2.2.1.3.1.1 - Additional Requirements

• Organizations responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, shall have documented expertise in influenza virology, immunology, structural biology, systems biology and systems immunology techniques, data management, assay development, vaccine discovery and development, adjuvant discovery and development, and a demonstrated knowledge of regulatory guidelines and submission processes for clinical testing of candidate vaccines.

• The Contractor shall conduct tasks in accordance with quality oversight that is appropriate to the phase of product development; under the appropriate level of biocontainment (BSL-2, BSL-3, BSL-4); and within all applicable and current Federal, state, and local laws, codes, ordinances and regulations, as well as all PHS Safety and Health provisions.

• The Contractor shall be responsible for the acquisition, care and housing of animals in an appropriate level bio-containment facility, and ensuring all work is conducted in accordance with the Animal Welfare Act and Public Health Service Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/phspol.htm), including the implementation of an animal care and use program and an animal use protocol approval process.

3.1.2.1.3.2 - Research Area 003 Component B: Vaccine Manufacturing and Toxicology Core

The objective of Research Area 003 Component B is to collaborate with the Vaccine Centers throughout the iterative vaccine design and development process, and provide expertise and state-of-the-art approaches to manufacture, formulate, http://grants.nih.gov/grants/olaw/references/phspol.htm optimize, and evaluate the safety and toxicity of innovative, cutting-edge vaccine platforms and approaches. Requirements include: (1) optimization, formulation and manufacturing of influenza vaccines and vaccine components in accordance with relevant FDA cGMP regulations and guidelines through approved release of product for use in clinical trials and human challenge studies; and (2) design and performance of IND-enabling GLP compliant (21 CFR 58) safety and toxicity testing of influenza vaccines and vaccine components as required prior to initiating clinical trials and human challenge studies.

1. Vaccine Manufacturing, Formulation and Delivery

• Work collaboratively with the Vaccine Centers throughout the pre-clinical development process to identify influenza vaccine products that pose considerable formulation and scale-up processes that would substantially impede development (e.g., candidate down-selection).

• Manage and conduct process development and cGMP production of influenza vaccines, vaccine components and critical reagents, including but not limited to peptides, recombinant proteins, nucleic acids, viral-like particles, viral vectors and attenuated organisms.

• Construct, screen and optimize influenza vaccine products for enhanced stability, immunogenicity and expression as well as other characteristics as directed.

• Develop scalable manufacturing processes of appropriate quality including cGMP-compliant production and purification processes suitable for Phase I/II clinical trials and human challenge studies.

• Manufacture products under cGMP conditions in compliance with FDA cGMP regulations and guidance for cGMP production, vialing or pre-filled applicator preparation, filling, finishing, packaging, labeling, storage and shipping of material.

• Perform innovative formulation studies, including mixing studies to support pre-clinical and clinical mixing processes.

• Perform all necessary release testing required for clinical use primarily as described for biologics and drugs in applicable FDA or International Conference on Harmonization (ICH) guidance and regulations, and provide a Certificate of Analysis.

• Establish, implement and oversee product-specific stability programs that primarily comply with FDA and/or ICH guidelines for cGMP manufactured vaccine products intended for human use.

• Develop and implement plans for stability testing of products including examination of titer and potency at appropriate intervals.

• In collaboration with the CIVICs SDMCC:

• Prepare Master Production Records including written production records for all steps in the production and purification processes for cGMP manufacture as well as the fill-finish of the product.

• Establish and maintain an inventory of all lots of manufactured products as well as reference standards in a manner that meets appropriate regulatory guidelines and store in accordance with regulatory guidelines. Maintain controlled storage of samples at appropriate temperatures with monitoring for equipment failure. Provide liquid nitrogen storage. Receive, store, ship and record products, master cell banks, biological agents, reagents, records and any other materials associated with the products.

• Provide all data, information and records required for the writing and submission of the Chemistry, Manufacturing and Controls (CMC) Information, ICH Quality documents, Master File and all other documents related to pre-Investigational New Drug (IND) and IND submissions or for submission to other non-U.S. regulatory authorities to the NIAID COR or to a COR-designated third party. Provide information pertaining to the composition, manufacture and quality control of the vaccine as appropriate for particular investigations carried out under an IND.

• Provide documentation for all regulatory submissions using appropriate formats for submission to Regulatory Agencies such as the FDA or other non-U.S. regulatory authorities.

• Retain all records and samples as indicated under cGMP guidelines and provide them to the NIAID COR upon request.

3.2.2.1.3.2.1 - Additional Requirements

• The Contractor shall conduct tasks in accordance with quality oversight that is appropriate to the phase of product development; under the appropriate level of biocontainment (BSL-2, BSL-3, BSL-4); and within all applicable and current Federal, state, and local laws, codes, ordinances and regulations, as well as all PHS Safety and Health provisions.

• The Contractor shall be responsible for the acquisition, care and housing of animals in an appropriate level bio-containment facility, and ensuring all work is conducted in accordance with the Animal Welfare Act and Public Health Service Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/phspol.htm), including the implementation of an animal care and use program and an animal use protocol approval process.

2. GLP Toxicology

• Work collaboratively with the Vaccine Centers to manage the design and conduct of safety and toxicity testing for vaccines throughout the pre-clinical development process.

• Perform IND-enabling pre-clinical safety and toxicity studies for vaccine products including:

• Systemic toxicity. Include dose-ranging studies of systemic and organ-specific toxicity, and acute and repeat toxicity.

• Local site reactivity studies. Include detailed clinical observations and histological evaluation of tissue at the injection or application site, or other visible lesions from biopsies or term necropsy samples.

• Biodistribution/Integration. In the case of specific products such as DNA and some vector-borne vaccines, perform studies to determine the biodistribution of the product. If the product persists above threshold levels in a tissue, perform an integration analysis.

• Genetic toxicity. In the case of specific products such as DNA and vector-borne vaccines, a pivotal GLP pre-clinical study shall focus on assessment for the potential of the nucleic acid vaccine to recombine with endogenous host DNA sequences and integrate into host chromosomes. Studies designed to address the potential for integration shall use the most sensitive methods available.

• Tumorigenicity studies. Tumorigenicity studies may be required under certain conditions; for example, if the pre-clinical genetic testing demonstrates evidence of integration activity and/or broad tissue distribution.

• Reproduction toxicity studies. Reproduction toxicity studies shall be performed prior to the use of products in pregnant women. Such studies shall include, for example, fertility, general reproductive performance, teratogenicity and developmental toxicity.

• Other studies. Includes other toxicity/safety studies and evaluation of vaccine components, adjuvants, alternate formulations, and delivery systems (e.g., induction of autoimmunity).

• In collaboration with the CIVICs SDMCC:

• Provide all data, information and records required for the writing and submission of Master File, Investigator’s Brochure, and all other documents related to pre-IND and IND submissions or for submission to other non-U.S. regulatory authorities to the NIAID COR or to a COR-designated third party.

• Provide information pertaining to the composition, manufacture and quality control of the product as appropriate for particular investigations carried out under an IND.

3.2.2.1.3.2.2 - Additional Requirements

• The Contractor shall conduct tasks in accordance with quality oversight that is appropriate to the phase of product development; under the appropriate level of biocontainment (BSL-2, BSL-3, BSL-4); and within all applicable and current Federal, state, and local laws, codes, ordinances and regulations, as well as all PHS Safety and Health provisions.

• The Contractor shall be responsible for the acquisition, care and housing of animals in an appropriate level bio-containment facility, and ensuring all work is conducted in accordance with the Animal Welfare Act and Public Health Service Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/phspol.htm), including the implementation of an animal care and use program and an animal use protocol approval process.

3.2.2.1.3.3 - Research Area 003 Component C: Clinical Core

The objective of Research Area 003 Component C is to design, implement and manage ethical and statistically sound clinical trials and human challenge studies for influenza vaccines, vaccine components and delivery systems developed by the Vaccine Centers. This includes early Phase I/II clinical trials to evaluate vaccine safety and immunogenicity, and human challenge studies to address questions related to influenza virus pathogenesis, immunity and correlates of protection, and down-select vaccine candidates for further development. Core activities also include processing specimens from clinical trials and human challenge studies for analyses by the Vaccine Centers and storing and maintaining study products and samples.

In coordination with the CIVICs Vaccine Centers and SDMCC, the Contractor shall:

• Design, execute and analyze results from Phase I clinical trials in healthy adult volunteers to evaluate vaccine candidates with promising pre-clinical safety and immunogenicity profiles including mix and match antigen/adjuvant approaches and head-to-head comparisons.

• Design, execute and manage Phase I/II clinical trials to evaluate vaccine candidates with promising pre-clinical safety and immunogenicity profiles from the above Phase I clinical trials in targeted age groups and at-risk populations.

• Design, execute and analyze results from human challenge studies in healthy adult volunteers (using challenge strains provided by NIAID) to evaluate promising vaccine candidates in comparison with licensed vaccines, and down-select candidates before moving into larger clinical trials.

• Develop Standard Operating Procedures (SOPs) for sample collection, processing and storage of clinical samples (e.g., from blood, mucosal wash fluids, mucosal tissues/cells, lymph node biopsies, bone marrow, microbiome).

• Design, execute and manage the longitudinal sampling of clinical specimens (e.g., from blood, mucosal wash fluids, mucosal tissues/cells, lymph node biopsies, bone marrow, microbiome) for immunological assessment of durable immunity and identification of correlates of protection.

• Maintain and operate controlled storage of samples, obtained from Clinical Core-led clinical trials and human challenge studies, at appropriate temperatures with monitoring and appropriate back-up storage for equipment failure. Activities include:

• Receipt, storage, shipment and recording of products, master cell banks, biological agents, reagents, records and any other materials associated with the investigational products, clinical trials and human challenge studies.

• Establishment and management of a specimen repository for storage of human samples from clinical trials and human challenge studies conducted by the CIVICs Clinical Core.

• In collaboration with the CIVICs SDMCC:

• Prepare all data and documents from clinical trials and human challenge studies in accordance with FDA regulatory requirements and standards.

• Ensure that all protocols and data are submitted in a timely manner for internal management and for reporting to NIAID as directed. This includes clinical sample collection; processing and storage protocols;

subject recruitment and retention information and meta-data; sample collection, processing, storage and availability; and all other relevant clinical trial and human challenge data (e.g., Adverse Events and Serious Adverse Events).

• Conduct primary assays as appropriate for Phase I/II clinical trials and human challenge studies under IND application.

3.2.2.1.3.3.1 - Additional Requirements

• Organizations responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, shall have documented expertise in the conduct of clinical trials and human challenge studies evaluating novel investigational vaccine candidates, including demonstrated knowledge of regulatory guidelines and regulatory submission processes for investigational products.

• The Contractor shall conduct tasks in accordance with quality oversight that is appropriate to the phase of product development; under the appropriate level of biocontainment (BSL-2, BSL-3, BSL-4); and within all applicable and current Federal, state, and local laws, codes, ordinances and regulations, as well as all PHS Safety and Health provisions.

• The Contractor shall document technical understanding and demonstrate evidence of capabilities to implement, conduct, analyze, complete and provide oversight for early phase clinical trials of novel vaccine candidates and human challenge studies in accordance with all local, state and Federal regulations.

• Access, recruit and retain clinical trial/study participants.

• Perform safety oversight procedures, including activities required prior to study initiation, study initiation, regulatory compliance (including IRB compliance and other regulatory compliance), FDA interactions, protocol amendments, protocol oversight, clinical site monitoring (including ISM and SMC members and interactions), safety reporting, data management and quality control, and audits.

• Adhere to current Good Clinical Practices (GCP).

• Provide for Quality Assurance/Quality Control (QA/QC), including ensuring all data generated meet regulatory and other required standards; and establishing, implementing and maintaining SOPs, processes for internal audits, remediation procedures, accommodation of independent auditors and procedures for study analysis and close-out.

• Receive, control and monitor storage, dispense and maintain inventory of study agents and clinical specimens.

• Classify, label, track and document all shipments of study agents and clinical specimens, adhering to International Transport Association requirements for shipping of dangerous goods.

• The Contractor shall demonstrate ability to develop study design elements, justifications, schedule events and timelines, perform safety assessments, and complete a safety plan, sample informed consent form, and template CRFs for clinical trials and human challenge studies.

• The Contractor shall demonstrate scientific knowledge, technical capabilities and previous experience (success/problem solving) in sample collection and processing for immunogenicity analyses; assay development and characterization; and subsequent testing of clinical trial samples.

• The Contractor shall collaborate with industry and clinical research support services contractors with respect to study design; statistical analysis;

preparation of and reporting study data for IND applications; data management and quality control; and clinical site monitoring.

• The Contractor shall demonstrate the availability, capacity, adequacy and suitability of the clinical research facilities, equipment and other resources for the conduct of clinical trials and human challenge studies.

-- END OF RESEARCH AREA 003 – TECHNICAL DESCRIPTION–

3.2.3 - RESEARCH AREA 003 - Additional Technical Proposal Instructions

The following information supplements Section 4 – Instructions, Conditions, and Notices to Offerors of this solicitation, and should be used for preparing proposals in response to Research Area 003.

Offerors must adhere to the following page limits when submitting a technical proposal (inclusive of CVs) under Research Area 003 The Collaborative Influenza Vaccine Innovation Centers (CIVICs)

Offerors must submit complete and separate proposals for each component that they are applying to:

Component A - Vaccine Center alone, Component B - Vaccine Manufacturing and Toxicology Core alone or Component C - Clinical Core alone.

Offerors may submit proposals for one or more of the above components; however, each component must be submitted as a sperate proposal. Do not combine separate components into one proposal. Pages extending beyond the technical proposal page limit for each Component listed below will be removed from proposals.

Component A: Vaccine Center 250 pages Component B: Vaccine Manufacturing and Toxicology Core 150 pages Component C: Clinical Core 150 pages

STATEMENT OF WORK FORMAT

Offeror(s) are required to provide a Statement of Work in their proposal. The Statement of Work shall be developed by each offeror based on the information in Section III of this solicitation, entitled “Research Areas and Technical Objectives”, and shall consist of two parts: (1) Scope, and (2) Technical Requirements. Provided below is an outline of the Statement of Work format that should be used by all offeror(s) in the preparation of their Technical Proposals. The headers and subheaders may be adjusted to match the requirements as proposed in each offeror’s individual technical proposal.

Contracts awarded as a result of this BAA will include the Statement of Work proposed by the offeror. Offeror(s) will be required to perform the activities and provide the resources appropriate to the scope of their specific negotiated Statement of Work.

The opening paragraph under the Technical Requirements section of the Statement of Work shall be followed by a description of all activities that the Contractor shall perform after the award of the contract. The Technical Requirements shall include all activities required to effectively implement the project and shall include a description of all items to be delivered to the Government during performance of the contract, such as progress reports, financial reports, end products, and other deliverables, along with a timetable for their delivery.

SAMPLE STATEMENT OF WORK

1. SCOPE

Instruction to offerors: Provide a brief description (one to two paragraphs) of the overall project and objectives in broad terms that indicates the size and magnitude of the proposed effort.

2. TECHNICAL REQUIREMENTS

[NOTE TO OFFEROR: The Technical Requirements shall begin with the following introductory paragraph.]

Independently, and not as an agent of the Government, the Contractor shall furnish all necessary services, qualified professional, technical, and administrative personnel, material, equipment and facilities, not otherwise provided by the Government under the terms of this contract, as needed to perform the tasks set forth below. Specifically, the Contractor shall provide:

This example is for Component A only and should be amended to fit for Components B and/or C in separate proposals as applicable.

A. Vaccine Center

1. Leadership and Project Management:

2. Vaccine Design and Development

3. Immunologic Analyses

4. Assay and Reagent Core

B. Project Management C. Communication and Contract Review Meetings D. Reports and Deliverables

3.2.3.1 - VACCINE CENTER

Technical proposals shall provide detailed descriptions of the rational, iterative design and pre-clinical evaluation of universal and improved seasonal influenza vaccine approaches, including:

a. Leadership and Project Management

• Processes for management of the Vaccine Center’s activities to achieve scientific milestones and timelines, including:

o Coordination and collaboration across Vaccine Design and Development and Immunologic Analyses teams to ensure incorporation of immunologic results in the iterative design of vaccine candidates.

o Coordination and collaboration with all activities of the Vaccine Center, as well as with other CIVICs Vaccine Centers and Cores.

o Procedures to address intellectual property issues.

o Plans for soliciting, evaluating, negotiating, awarding and managing subcontracts in accordance with FAR Clause 52.244-2 (if applicable), including a description of experience with identification and remediation of subcontractor performance problems or noncompliance with subcontract terms and conditions.

• Plans for delineating the processes and approaches to establish priorities;

develop and review new research activities within the Center; identify and select immunogen/vaccine constructs for cGMP manufacturing and clinical studies; and discontinue support of unproductive or unneeded research activities.

• Plans to organize a post-award contract initiation meeting. Discuss plans to organize annual review meetings to provide a thorough assessment of progress; problems and approaches to their resolution; and future plans.

• Plans to develop and manage a pilot and cross-Center research program including examples of collaborative projects that could bring multidisciplinary approaches to advance influenza vaccine research and development.

• Gantt chart summarizing the scientific milestones and timelines.

Milestones must be quantitative and reflect key criteria of success and tangible outcomes of each activity and sub-activity for each required element. NOTE: Milestones and timelines may be revised during negotiations with NIAID.

b. Vaccine Design and Development

• Description of at least three unique candidate universal influenza vaccine approaches to be evaluated, including data supporting induction of broadly protective, durable immunity.

• Methods for rational iterative vaccine design, addressing immunogens, adjuvants, platforms and delivery systems to achieve broadly protective, durable immunity.

• Plans and procedures for improving seasonal influenza vaccine efficacy.

• Strategy for pre-clinical evaluation of vaccine approaches in combination and head-to-head comparisons, including approaches developed from other NIAID or externally-supported programs.

• Plans to iteratively refine and optimize vaccine approaches based on data from pre-clinical studies, clinical trials and human challenge studies.

c. Immunologic Analyses

• Methods for pre-clinical analysis of universal and improved seasonal influenza vaccine candidates, including:

o Justification of the animal model(s) selected for pre-clinical efficacy and immunological analyses including strengths and weaknesses of the model and any proposed improvements to the model, if applicable.

o Explanation of how the proposed studies will improve the predictive value of the animal model(s) for evaluating universal and improved seasonal influenza vaccine efficacy.

o Strategy for testing and evaluation of vaccine/adjuvant formulations and routes of vaccination using pre-clinical animal immunization and challenge models.

o Types of pre-clinical efficacy and immunological analyses to be conducted, including high-throughput analyses and/or other advanced technologies to achieve program goals.

o Plans for in vitro and/or ex vivo characterization of human anti-influenza responses.

o Plans for addressing the impact of pre-existing immunity and sequential/repeat vaccination on pre-clinical study design and interpretation of study results.

• Analysis of human samples obtained from the Clinical Core or independently-funded clinical studies/trials.

o Description of the clinical samples required for complete immunologic characterization of vaccine-specific immune responses, including:

Sample type and collection, handling and storage specifications required to preserve critical components to be analyzed.

Optimal frequency and timing for collection of clinical samples, both pre- and post-vaccination.

Types of meta-data (e.g., age, sex, medical history, etc.) that should be collected for each sample type.

o Plans for addressing the impact of pre-existing immunity and sequential/repeat vaccination on cohort selection and interpretation of study results.

o Procedures for quantitative and qualitative evaluation of human B cell, T cell and innate…