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HIV Vaccine Strategies

Solicitation Number: S09-202
Agency: Department of Health and Human Services
Office: National Institutes of Health
Location: National Cancer Institute
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S09-202
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Combined Synopsis/Solicitation
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Added: Jul 24, 2009 4:13 pm

HIV Vaccine Strategy -SOW

A. Background Information


In order to enhance the efficacy of our current HIV vaccine strategies, we plan to incorporate an antibody-based HIV vaccine with three separate HIV vaccine strategies developed by the NCI Vaccine Branch to prevent HIV infection and transmission. Binding antibodies are reliably detected in most of the macaques vaccinated with many of our HIV vaccine strategies, whereas neutralizing antibodies are rarely, or even if detected, usually of a low titer and narrow in their breadth. It is generally believed that an effective HIV vaccine will have to elicit antibodies that react against highly conserved domains on the HIV envelope. Devico et al found that epitopes located in and around the coreceptor binding site of HIV-1 envelope glycoprotein (gp120), which exhibit enhanced exposure after attachment to the CD4 receptor and comprise some of the most conserved and functionally important residues on the viral envelope, could elicit antibodies in vaccinated macaques and clear plasma viremia in contrast to unvaccinated control animals. Based on this conclusion, a collaborative program was established to test the immunogenicity and protective efficacy of the three different HIV vaccine strategies developed by the NCI Vaccine Branch, each incorporating the antibody-based CD4 receptor-inducible epitope Full-Length Single Chain (FLSC) vaccine.


B. Purpose and Objectives


There are 3 projects that comprise this collaborative study all using some form of an AIDS vaccine candidate called full length single chain or FLSC. Project one involves a mucosal & nanoparticle vaccine; Project two involves a DNA/protein vaccine using in vivo electroporation as DNA delivery methodology and Project three involves an adenovirus vector prime/envelope protein boost vaccine strategy.


Project one has three purposes for this study. The main one is to test the concept that a T-cell based mucosal vaccine combined with an antibody-based mucosal vaccine will generate better immunity to prevent HIV transmission and infection at the site of entry, or if the virus is transmitted, to slow the development of AIDS. If most of the virus inoculum is neutralized by secretory IgA, and thus the initial mucosal nidus of infection is small, it may be possible for mucosal memory CD8+ T cells to respond fast enough to eradicate this initial nidus before it replicates to levels necessary to spread to the lymph nodes and then the bloodstream. Thus, the goal is to nip the infection in the bud and prevent establishment of systemic infection. The second purpose of this study is to test a new technique for delivering the vaccine. Much of our vaccine strategies have involved intrarectal immunization, which we found to be one of the most effective routes for inducing mucosal immunity. To develop a way to accomplish the same goal via the oral route, one approach we are currently exploring is to deliver nanoparticles containing the vaccine encapsulated in microparticles that can pass through the stomach acid intact and release their nanoparticle contents at a pH characteristic of an appropriate level of the small or large intestine. The third purpose is to test either heterologous challenge or a therapeutic vaccine depending on the results of the preventative vaccine study. If most of the monkeys have been protected, we will re-challenge the monkey with SIVmac251 to examine whether the vaccine-induced protection is persistent long enough to protect against a heterologous challenge. If most of the monkeys turn out to be infected, then we will test our peptide-based therapeutic vaccine under ART.


Project two will examine the immunogenicity induced by DNA vaccine boosted by rhFLSC protein. The DNA vaccine is delivered by in vivo electroporation using a mixture of plasmids that contain rhFLSC DNA in addition to plasmids expressing gag, pol, nef, tat vif. The purpose of these experimental arms is to compare immunogenicity of DNA only vs DNA coinjected with protein, or the protein is given as boost. Using intramuscular vs intradermal delivery of DNA will allow to directly compare the quantity and quality of the induced immune responses. The following 4 arms will be tested: DNA vaccine is delivered intramuscularly (1), DNA is coinjected with env-CD4 protein (2), DNA is given a prime followed by protein boosts (3), DNA is coinjected intradermally with env-CD4 protein (4). This project will also examine the efficacy of the induced immune responses upon challenge by SHIV SF162P4.


Project three involves the induction of humoral, cellular and mucosal immunity, and protective efficacy by a replicating Ad-recombinant prime/FLSC boost strategy. This project will examine if (1) priming with a replicating Ad 5 host range mutant (Ad5hr)-HIV recombinant encoding the rhFLSC gene and boosting with rhFLSC protein will elicit broadly neutralizing antibodies and potent protection;(2) priming with an Ad5hr-HIVBalgp160 recombinant will elicit broader antibody responses and better cellular immunity than priming with Ad5hr-HIVBalrhFLSC;(3) the prime boost approach will elicit a wide spectrum of immune responses, including envelope-specific cellular immunity in peripheral blood and mucosal sites, and systemic and mucosal antibodies with neutralizing and other functional activities; (4) the prime/boost approach will result in protection against a heterologous SHIVSF162P4 rectal challenge.


C. Overall Requirements


The Subcontractor shall furnish all necessary services, qualified personnel, material, equipment and facilities as needed to perform the work outlined below:
1) Provide a well-equipped and maintained animal facility for the maintenance of up to 106 non-human primates (Indian rhesus macaques). Animals will be initially held at biosafety level one (BSL-1) until containment at biosafety level two (BL-2) with biosafety level three (BL-3) practices are required due to experimental infection with biohazardous agents.
2) Put the animals through appropriate quarantine and testing.
3) Provide housing, veterinary care and routine health surveillance for all animals maintained under this Subcontract seven days a week as necessary. Provide veterinary care for all animals in accordance with (1)"Guide for the Care and Use of Laboratory Animals", DHHS (NIH 85-23, (2)"Animal Welfare (DHHS-TN 73-2); (3) NIH Manual "Responsibility for Care and Use of Animals", Issuance 4206 and 6000-3-4-58, and (4) Public Health Services Policy on Humane Care and Use of Laboratory Animals.
4) Provide caging of the size and configuration to meet current USDA/APHIS standards and requirements for the housing of NHP's, including those animals requiring BL2/BL3 containment.
5) All manipulations will be performed as directed by the NCI Project Managers for the 3 specific projects. Blood samples will be collected according to a schedule provided by the NCI Project Managers for the 3 specific projects. Some samples will be analyzed by the Subcontractor for Complete Blood Count (CBC, including determination of CD4, CD8 cells, serum and chemistry) and the data will be sent to the project manager. Other blood samples will be either directly shipped to project manager or sent as isolated live-frozen PBMCs and plasma. Plasma viral load, antibody titers, drug treatment, vaccination, infection, any other necessary treatments, and necropsies will be performed as specified by the NCI Project Managers.
6) Provide and conduct clinical laboratory testing for analysis of animal materials (such as complete blood counts, parasite evaluations, and bacterial culture and serum chemistry tests) as required for appropriately monitoring the animals' health and treating any occurrences of disease.
7) Provide technical assistance and veterinary assistance as needed for performance of all procedures required by research protocols such as inoculation and bleeding of the animals, collection of saliva, vaginal lavage fluid, rectal secretions, bone marrow, bronchial alveolar lavage(BAL) and provide professional veterinary assistance for performance of all surgical procedures (such as intestinal resections, laparotomy for colonic wedge resection, vaginal, colonic and rectal pinch biopsies, lymph node biopsies, jejunal endoscopy) and complete post-mortem examinations.
8) Maintaining, and monitoring of an estimated total of 106 macaques until all 3 studies comprising this collaborative study are complete (estimated duration of 18 months). The work and effort obligated to meet the requirements of this SOW are subject to the needs of SAIC-F's client, SAIC-F's needs, the Subcontractor's performance, and the availability of funds for this project.
9) Infect animals with viruses or recombinant viruses as specified by the NCI Project Managers. Appropriate BL2/BL3 laboratory space must be available for preparation of inocula, filling of injection devices and other biohazardous sample handling.


10) Any additional information regarding possible pathologic changes in the animals must be reported immediately to the NCI Project Manager, and SAIC-F Contract Manager's Technical Representative (SAIC-F COTR). In case euthanasia of animal is necessary due to any health problems, necropsy will be performed on the animals by the Subcontractor according to protocols provided by the individual project managers. The necropsy report will be provided directly to the NCI Project Manager. Necropsy report will include pathologic tissue analysis as requested by the Project Manager. Tissue samples requested should be taken and sent to the Project Manager as specified, and may include tissue snap frozen on dry ice, fixed in formalin, and/or provided fresh and sterile in media. Tissues requested may include: right and left axillary and inguinal lymph nodes, liver without gall bladder, duodenum, jejunum, ileum, large bowel; mesenteric and colonic lymph nodes and spleen; rectal/vaginal/cervical tissue. If necessary this list may be modified and changes provided to the Subcontractor. In addition, clotted blood, fresh heparinized blood, BAL and GALT samples may be requested and should be sent to the individual NCI Project Manager within one hour of harvest.
11) The Subcontractor must provide the PHS Assurance number of the animal facility where the animals will be housed in their proposal. The Subcontractor must identify the veterinarian(s) providing animal care. The Subcontractor must indicate accreditation status by AAALAC and confirm activity of an Animal Care and Use Committee.
12) Deliver blood and tissues from animals under sterile and viable conditions to the NCI Project Manager within one hour after processing as specified by the NCI Project Manager.
13) The Subcontractor will identify invoices according to project, with specific reference to the contract number as stated in other terms and conditions in this Subcontract.
14) All materials and equipment supplied by the NCI Project Managers to the Subcontractor in support of these studies will be returned to the NCI Project Managers after the tasks are completed or destroyed as directed by the NCI Project Managers. The Subcontractor must submit proper documentation to the SAIC-F Contracting Officer certifying the date of destruction of materials not being returned within fourteen (14) days of the action.


Project 1 Specific Requirements


Title: Development of mucosal HIV vaccines (Nanoparticle vaccine)


Animal technical procedures
• Vaccination by oral, gastric gavage, or intrarectal routes
• Infection of animals with viruses or recombinant viruses
• Colonic and rectal pinch biopsies
• Laparotomy for colonic wedge resection and collection of mesenteric lymph nodes
• EDTA blood and plasma collection
• Intrarectal immunizations (IR) and intrarectal challenge
• Vaginal pinch biopsy and vaginal lavage
• Rectal lavage and fecal specimen collection for antibody assays
Necropsy will be performed as specified by the NCI Project Managers.


Assays: (performance of any assays requires experienced validated service)
• Plasma viral load
• Antibody titers by ELISA against SIV proteins
• CD4-inducible neutralization assays and conventional neutralization assays
• IFN ELISPOT(gag/pol/tat/nef/vif/env)
• Micro-array Analysis
• Histology
• Immuno-histo-chemistry (IHC)
• CD4 counts


• multicolor intracellular cytokine staining on fresh or live frozen PBMC for gag, pol, env, nef, tat, vif, and gag tetramer on mamu A*01+ animals: CD3, CD8, CD4, IFNg, TNFa, IL-2; CD45Ra, CD28, CCR7
• multicolor intracellular cytokine staining on isolated cells from rectal and vaginal pinches


Project 2 Requirements


Title: Protective Immunity Elicited by SIV gp120-CD4 Immunogens (DNA protein vaccine
using electroporation)


Animal technical procedures:
• Vaccination will be performed using in vivo electroporation (intramuscular and intradermal) and includes intramuscular and intradermal protein delivery
• Collection of EDTA blood and plasma collection
• Preparation of live-frozen PBMC
• Mucosal samplings
• Collection of saliva and rectal swabs
• Collection of Bronchial alveolar lavage (BAL)
• Preparation and collection of live cells from BAL; collection of BAL wash
• Preparation of live cells from rectal pinches from A*01 positive animals only
• Intrarectal challenge 4 month after last vaccination (month 10 of study)
• Collection of tissues at necropsy will be specified


Assays: (performance of any assays requires experienced validated service)
• selected Elispot assay, to be specified by the PIs to map epitops
• multicolor intracellular cytokine staining on fresh or live frozen PBMC for gag, pol, env, nef, tat, vif (using pools of 15-mer peptides overlapping by 11 aa), and gag tetramer on mamu A*01+ animals: CD3, CD8, CD4, IFNg, TNFa, IL-2; CD45Ra, CD28, CCR7
• multicolor intracellular cytokine staining on isolated cells from BAL, as above:
• multicolor intracellular cytokine staining on isolated cells from rectal pinches on mamu A*01+ animals only: gag tetramer see above
• binding antibody ELISA for gag, nef, SF162env including HIV-specific IgA and IgG
(plasma, BAL wash, saliva, rectal swab)
• neutralizing antibody (CD4i)
• Virus load
• CD4 count


Project 3 Requirements


Title: Investigation of Ad-HIVenv prime/rhFLSC boost vaccines


Animal technical procedures
• Intranasal, Intratracheal, and Intramuscular immunizations
• Intrarectal challenge
• Collection of Bronchial alveolar lavage(BAL) , bone marrow, jejunal endoscopy, LN biopsies
• Serum collection and EDTA blood collection
• Collection of rectal/vaginal secretions
• Rectal/vaginal pinches


Assays: (performance of any assays requires experienced validated service)
• ELISAs and ELISA capture assays for binding antibody in serum (rhFLSC, Bal gp160, rh CD4, SF162 gp160)
• Competitive binding ELISAs for epitope identification
• Assay for CD4i neutralization
• IFN-γ ELISPOT, Proliferation by CFSE on fresh cells and ICS polyfunctional central and effector CD4 and CD8 memory cells
• Plasma and tissue virus load
• CD4 counts


DATA RECORDS


A computer based record keeping system with the capability to send and receive data between the Subcontractor and investigators at both NIH and NCI-Frederick should be available.


DATA DELIVERABLE


In addition the following information will be provided to the SAIC-F Contracting Officer's Technical Representative (SAIC-F COTR)/Investigator. Reporting Requirements and Deliverables:


• vendor health reports submitted quarterly
• "in-house" animal health reports (serology, bacteriology, parasitology) on a quarterly basis, for all animals housed under the contract
• sick animal report from the veterinarian to include history, diagnosis and treatment
• an animal inventory with each monthly statement for all animals housed under the Subcontract to be provided to the SAIC-F COTR and the investigator
• a break down of all technical procedures for all species housed under this Subcontract will be provided to the SAIC-F COTR and the investigator each month
• copies of approved animal experimental protocols supported by the Subcontractor's IACUC shall be submitted to the NCI PO within 20 working days of their approval
• research summaries and various other reports as required


AAALAC ACCREDITATION/ PUBLIC HEALTH SERVICE ASSURANCE


Offerors shall be registered with the Office of Laboratory Animal Welfare (OLAW) and submit an assurance number with the proposal. This is a mandatory requirement. Failure to provide an assurance number may cause any proposal submitted to be non-responsive to the solicitation requirements. Offerors must maintain full accreditation by AAALAC. Failure to do so may cause any proposal submitted to be non-responsive to the solicitation requirements.


HAZARDOUS AGENTS


The Subcontractor will be responsible for compliance with all relevant safety and environmental regulations, including the disposal of chemical, medical and radioactive waste. The Subcontractor shall provide a Chemical Hygiene Officer, Chemical Hygiene Plan, etc. as described in 29 CFR 191.1450. Material Safety Data Sheets, records and other related information must be maintained at the Subcontractor's site. Spill response and cleanup will be the Subcontractor's responsibility.


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S09-202 RFP Cover Page

Type:
Other (Draft RFPs/RFIs, Responses to Questions, etc..)
Label:
S09-202 RFP Cover Page
Posted Date:
July 24, 2009
Description: Please refer to this document for Key detailed instructions for Offerors. Failure to abide to the instructions contained within the document could be interpreted as a non-responsive offer.
:
Bldg 427, Room 12
Frederick, Maryland 21702
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Subcontractor's location.

United States
:
Howard Souder, Jr.,
Subcontract Specialist
Phone: 301-846-5096
Fax: 301-228-4037