RFP_2014-N-16464_06-18-14.pdf

PAGES

15A. NAME

AND

ADDRESS

OF

OFFEROR

SEC. PAGE(S) SEC. PAGE(S)

(Date) (Hour)

CALENDAR DAYS

14. ACKNOWLEDGMENT OF AMENDMENTS

(The offeror acknowledges receipt of amend-ments to the SOLICITATION for offerors and related documents numbered and dated:

(Type or Print)

SOLICITATION, OFFER AND AWARD 1. THIS CONTRACT IS A RATED ORDER

UNDER DPAS (15 CFR 700)

RATING

PAGE OF

1 80

2. CONTRACT NO.

3. SOLICITATION NO.

2014-N-16464

4. TYPE OF SOLICITATION

SEALED BID (IFB)

X NEGOTIATED (RFP)

5. DATE ISSUED

06/18/2014

6. REQUISITION/PURCHASE

NO.

00HCVJH1-2014-68463

7. ISSUED BY CODE 8219 8. ADDRESS OFFER TO (If other than Item 7)

Centers for Disease Control and Prevention (CDC)

Procurement and Grants Office (PGO)

2920 Brandywine Road

Atlanta, GA 30341-5539

Approved as to Form and Legality: _____________________________

NOTE: In sealed bid solicitations “offer” and “offeror” mean “bid” and “bidder.”

SOLICITATION

9. Sealed offers in original and 4 copies for furnishing the supplies or services in the Schedule will be received at the place specified in Item 8, or if handcarried, in the depository located in 2920 Brandywine Road, Colgate Bldg, Security Desk until 2:00p local time 07/18/2014

CAUTION -- LATE Submissions, Modifications, and Withdrawals: See Section L, Provision No. 52.214-7 or 52.215-1. All offers are subject to all terms and conditions contained in this solicitation.

10. FOR INFORMATION

CALL:

A. NAME

Kim Morris

B. TELEPHONE (NO COLLECT CALLS)

AREA CODE NUMBER: EXT:

(770) 488-2621

C. E-MAIL ADDRESS

ycy1@cdc.gov

11. TABLE OF CONTENTS

(x) DESCRIPTION (x) DESCRIPTION

PART I – THE SCHEDULE PART II – CONTRACT CLAUSES

X A SOLICITATION/CONTRACT FORM 1 X I CONTRACT CLAUSES 52

X B SUPPLIES OR SERVICES AND PRICES/COSTS 2 PART III - LIST OF DOCUMENTS, EXHIBITS AND OTHER ATTACH.

X C DESCRIPTION/SPECS./WORK STATEMENT 3 X J LIST OF ATTACHMENTS 56

X D PACKAGING AND MARKING 27 PART IV – REPRESENTATIONS AND INSTRUCTIONS

X E INSPECTION AND ACCEPTANCE 28 REPRESENTATIONS, CERTIFICATIONS, AND

X F DELIVERIES OR PERFORMANCE 29 X K OTHER STATEMENTS OF OFFERORS 57

X G CONTRACT ADMINISTRATION DATA 31 X L INSTRS., CONDS., AND NOTICES TO OFFERORS 58

X H SPECIAL CONTRACT REQUIREMENTS 38 X M EVALUATION FACTORS FOR AWARD 76

OFFER (Must be fully completed by offeror)

NOTE: Item 12 does not apply if the solicitation includes the provisions at 52.214-16, Minimum Bid Acceptance Period.

12. In compliance with the above, the undersigned agrees, if this offer is accepted within calendar days (60 calendar days unless a different period is inserted by the offeror) from the date for receipt of offers specified above, to furnish any or all items upon which prices are offered at the price set opposite each item, delivered at the designated point(s), within the time specified in the schedule.

13. DISCOUNT FOR PROMPT PAYMENT

(See Section I, Clause No. 52-232-8)

10 CALENDAR DAYS

20 CALENDAR DAYS

30 CALENDAR DAYS

AMENDMENT NO. DATE AMENDMENT NO. DATE

CODE FACILITY 16. NAME AND ADDRESS OF PERSON AUTHORIZED TO SIGN OFFER

15B. TELEPHONE NO.

AREA CODE NUMBER EXT.

15C. CHECK IF REMITTANCE ADDRESS

IS DIFFERENT FROM ABOVE - ENTER

SUCH ADDRESS IN SCHEDULE.

17. SIGNATURE

18. OFFER DATE

AWARD (To be completed by Government)

19. ACCEPTED AS TO ITEMS NUMBERED 20. AMOUNT

22. AUTHORITY FOR USING OTHER THAN FULL AND OPEN COMPETITION:

21. ACCOUNTING AND APPROPRIATION

10 U.S.C. 2304(c)( ) 41 U.S.C. 253(c)( )

23. SUBMIT INVOICES TO ADDRESS SHOWN IN

(4 copies unless otherwise specified)

ITEM

24. ADMINISTERED BY (If other than Item 7) CODE 2536 25. PAYMENT WILL BE MADE BY CODE 434

Centers for Disease Control and Prevention

Acquisition and Assistance Branch 1

2920 Brandywine Road, MS E-15

Atlanta, GA 30341-5539

Centers for Disease Control and Prevention (FMO)

PO Box 15580 404-718-8100

Atlanta, GA 30333-0080

26. NAME OF CONTRACTING OFFICER (Type or print)

27. UNITED STATES OF AMERICA

(Signature of Contracting Officer)

28. AWARD DATE

IMPORTANT -- Award will be made on this form, or on Standard Form 26, or by other authorized official written notice.

AUTHORIZED FOR LOCAL REPRODUCTION STANDARD FORM 33 (REV. 9-97)

PREVIOUS EDITION IS UNUSABLE Prescribed by GSA

FAR (48 CFR) 53.214©

K

SECTION B - SUPPLIES OR SERVICES AND PRICES/COSTS

ITEM SUPPLIES / SERVICES QTY/UNIT UNIT PRICE EXTENDED PRICE

0001 A Prospective Clinical Trial to Determine the Seroconversion and Immunogenicity of Hepatitis A Vaccine Starting at 15 Days Post- Vaccination in Persons Age > 40 Years

September 2014 – September 2017

36 Months

B.1. Brief Description of Supplies or Services

The Department of Health and Human Services (HHS), Centers for Disease Control and Prevention (CDC), National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), requires the services of a Contractor to design and conduct clinical vaccine trials among older adults to assess the immune response to hepatitis A vaccine in accordance with possible use for post-exposure prophylaxis.

B.2. Estimated Cost and Fixed Fee

a. The estimated cost of this contract is $_________.

b. The fixed fee for this contract is $ ______. The fixed fee shall be paid in installments based on the percentage of completion of work, as determined by the Contracting Officer, and subject to the witholding provisions of the clauses ALLOWABLE COST AND PAYMENT and FIXED FEE referenced in Section I, Contract Clauses of this contract.

c. The total estimated amount of the contract, represented by the sum of the estimated cost plus the fixed fee is

B.3. Performance-Based Preference

Pursuant to FAR 37.102(a) (2), the Contracting Officer will use performance-based acquisition methods to the maximum extent practicable.

Title of Project: A Prospective Clinical Trial to Determine the Seroconversion and Immunogenicity of Hepatitis A Vaccine Starting at 15 Days Post-Vaccination in Persons Age > 40 Years

SECTION C - DESCRIPTION/SPECIFICATION/PERFORMANCE WORK STATEMENT

C.1. Background and Need

A long history of post-exposure prophylaxis with immune globulin G (IG) demonstrates moderately high (~85%) protective efficacy against clinically apparent hepatitis A virus (HAV) infection when IG is received within 2 weeks of exposure to, e.g., a hepatitis A virus infected person, or HAV contaminated food or water (Victor, 2007). Based largely on the results of two randomized, controlled trials (see below), the Advisory Committee on Immunization Practices (ACIP) in 2007 recommended hepatitis A vaccine for post-exposure prophylaxis against HAV for healthy persons aged 12 months to 40 years. Vaccination is to be administered as soon as possible, but within 2 weeks after exposure. Vaccination for post-exposure prophylaxis compared to IG has the advantage of inducing long-term protection, and hepatitis A vaccine is often more readily available than IG for immediate use. Since the two trials did not include adults ages > 40 years, ACIP recommended IG for older adults, but indicated that hepatitis A vaccine can be used for post-exposure prophylaxis if IG cannot be obtained. ACIP recommends IG for immunocompromised persons, persons who have chronic liver disease, and persons with contraindications to receiving hepatitis A vaccine.

The design and results of the two trials that provide the evidence for these ACIP recommendations are informative. One of the trials was conducted in Naples, Italy (Sagliocca, 1999). Household contacts > 1 to < 40 years of age (351) from 148 households with persons hospitalized for acute hepatitis A were randomized to receive hepatitis A vaccine (173) or no vaccine (178) for prophylaxis. The study had several important limitations including wide confidence intervals, use of anti-HAV IgM as an endpoint for hepatitis A virus infection in vaccinated contacts (which would not distinguish between infection and vaccination), and use of unvaccinated contacts as the control group rather than comparing outcomes with vaccination to outcomes with administration of IG. Nonetheless, the investigators concluded that hepatitis A vaccine is effective prophylaxis for secondary acute hepatitis A infection if given within two weeks of exposure.

Victor et al. reported the results of a similarly designed study conducted in Almaty, Kazakhstan (Victor 2007). Subjects were ages 2-40 years. Household and day care contacts (1090) of acute hepatitis A cases were randomized to receive hepatitis A vaccine (568) or IG (522) within 2 weeks of exposure to the case.

Since a placebo control group could not be included for ethical reasons, prophylactic efficacy of hepatitis A vaccine was estimated using assumptions of IG efficacy at 90% and 80%. Hepatitis A vaccine prophylactic efficacy was 86% (95% CI, 73-93) and 73% (95% CI, 47-86), respectively, using these assumptions. The investigators concluded that either hepatitis A vaccine or IG provides good protection after exposure to hepatitis A, in persons 2-40 years of age.

The results of the two studies formed the basis for ACIP recommendations for hepatitis A vaccine in post-exposure prophylaxis of HAV for persons 1-40 years of age, if administered within 2 weeks of exposure.

The efficacy of human, blood-derived IG, or hepatitis A vaccine when administered greater than 2 weeks after exposure has not been established.

A recent study in the Netherlands also assessed the efficacy of vaccine in exposed adults (Whelan, 2013).

In this study the efficacy of vaccine <8 days post-exposure was examined in healthy adults in two age groups (< 30 years and 30-50 years). The study identified 7 secondary cases of 100 vaccinated within 8 days of exposure who had follow-up blood samples; the 7 included 3% of subjects ≤ 15 years of age (2/58), 6% (2/32) aged 16-40 years, and 30% (3/10) aged > 40 years. IG instead of vaccine was given to 24 subjects at high risk of infection; of the 11 subjects followed (median age 39), no secondary cases were found. The investigators concluded that vaccine for hepatitis A post-exposure prophylaxis should be limited in older adults, and IG should be the prophylaxis of choice. Follow-up blood samples were available from a limited number of older adults (10) in this study.

Multiple studies have evaluated hepatitis A vaccine seroprevalence and immunogenicity within 2 weeks of administration in healthy adults who were anti-HAV negative and unexposed to hepatitis A virus.

Immunoglobulin M (IgM) antibody to hepatitis A virus (anti-HAV) is detectable in most vaccinated young adults (94%) at 2 weeks after vaccination (Vidor, 1996). However, the contribution of IgM to protection within two weeks of vaccination is unclear, and the minimum concentration of anti-HAV IgM that correlates with protection is not known (Lemon, 1997). The role of anti-HAV immunoglobulin G (IgG) in protection is better studied. A concentration of vaccine-induced anti-HAV IgG ≥20mIU/mL has served as a correlate of protection, although 10 mIU/mL has also been considered a protective level in some post-vaccination studies (Reuman, 1997). It has been proposed that any detectable concentration of IgG anti- HAV may even suggest protection (Stapleton, 1995).

Shouval, et. al studied the immunogenicity and anti-HAV antibody kinetics of inactivated hepatitis A virus vaccine (25ng dose) compared to IG in a small sample of healthy adults (age range 18-50 years for IG; 20- 27 years for vaccine ). [Note: The current licensed vaccine for adults VAQTA contains 50U of viral antigen.] The results showed that 80%, 93%, and 100% of vaccine recipients (n=19) seroconverted (radioimmunoassay signal/cut-off ≤ 1) within 14 days, 3 weeks, and 5 weeks post-vaccination, respectively. In comparison, all of the IG recipients (n=30) seroconverted during the week after injection and 92% remained positive at week 4. GMTs of total anti-HAV in vaccine recipients rose from 19 mIU/mL at day 0 (after vaccine) to 54 mIU/mL at week 2. In comparison, for IG recipients GMTs of total anti-HAV level were 107mIU/mL at day 7 and 54mIU/mL at 4 weeks (there was no week 2 level). The study showed that administration of a single 25 ng dose of hepatitis A vaccine, though half the dose that is currently used, led to a rapid rise in anti-HAV in all healthy young adults, and antibody levels after the first injection reached levels similar to or higher than levels for IG recipients by 4 weeks. See figure below.

Similar kinetic studies in older adults are lacking.

Pooled data from three clinical trials in healthy adults (18-62 years) evaluating the immunogenicity of 1,440 EL.U. of inactivated hepatitis A vaccine (HAVRIX, Smith-Kline Beecham Biologicals, Rixensart, Belgium) were reported by Van Damme et al. (Van Damme, 1994). Seroconversion (≥ 20 mIU/mL) proportions were 88% at 14 days, and 99% at one month after a single vaccine dose. Age groups were not further delineated in these studies. When considering post-exposure prophylaxis for persons age >40 years, these studies demonstrate that additional immunogenicity data are needed to determine the response to hepatitis A vaccine at the short interval after administration.

A small number of trials report the immune responses to hepatitis A vaccine among older adults at approximately 2 weeks after the first dose. Williams et. al. (2000) evaluated vaccine-induced seroconversion proportions (anti-HAV IgG ≥ 20 mIU/mL) at 15 days post-vaccination among adult employees (mean age 40) of the Alaska Native Medical Center. Subjects received 1440 EL.U of HAVRIX via jet-injector or standard intramuscular (IM) administration. The seroconversion proportions were 80% and 71%, and the geometric mean titers (GMT) were 43mIU/mL and 29 mIU/mL for jet-injector and IM administration, respectively. In an published sub-analysis from this study, the age-related seroconversion proportions for 15 and 30 days after hepatitis A vaccine dose one were: 74% (n=125) and 90% (n=128) for ages 40-49 years; 54% (n=37) and 81% (n=42) for ages 50-59 years; and 30% (n=10) and 50% (n=10) for ages ≥ 60 years. At 15 and 30 days, the GMTs (mIU/mL) were: 26.09 (n=125) and 87.97 (n=121) for ages 40-49; 12.80 (n=37) and 39.70 (n=41) for ages 50-59; and 1.62 (n=10) and 4.49 (n=9) for age ≥ 60, respectively (Nelson, 2014). These results suggest hepatitis A vaccine protection might be achieved at 15 days post-vaccination for many older adults, but the sample sizes were too small by age group for definitive conclusions.

Briem et al. examined seroconversion (≥20 mIU/mL anti-HAV) proportions and GMTs at day 15 post-vaccination with 1440 EL.U-HAVRIX in two age groups. At day 15, 90% of 134 adults ages 20-39 (mean 30) years seroconverted, and 77% of 68 adults ages 40-62 (mean 48) years seroconverted (p <0.05). The GMTs at day 15 were similar in both age groups, 282 mIU/mL for persons ages 20-39 years, and 262 mIU/mL for ages 40-62 years, although the difference was statistically significant (p<0.001). The investigators also evaluated the responses at1 month and 6 months post-dose 1. They reported seropositivity rates comparable in both age groups, suggesting similar final responses to the first dose of hepatitis A vaccine, but achieved at a slower rate in the older age group. Seropositivity rate was defined as the number antibody positive divided by the number tested expressed as a percent. The investigators concluded hepatitis A vaccine could be used for rapid vaccination in older adults (Briem and Safary, 1994).

Reuman et al. studied the serologic response (proportion of subjects demonstrating > 10 mIU/ml seroresponse) among adults age < 40 (18-39 years) and age ≥ 40 years stratified to receive formalin inactivated, alum-adjuvanted hepatitis A vaccine, which contained 25U of viral antigen. [Note: The current licensed vaccine for adults (VAQTA, Merck & Co., Inc, Whitehouse Station, NJ contains 50U of viral antigen.] Doses were administered at 0 and 24 weeks for both age groups. Serologic response rates, measured at two weeks after the first dose, were low for subjects age ≥ 40 years (23%; 5/22), compared to rates in the < 40 age group (60%; 15/25). The serologic response improved at one month to 91% and 70% for adults in the < 40 and ≥ 40 age groups, respectively. Mean GMTs were 6.1 mIU/mL at two weeks post-vaccination for the ≥ 40 age group compared to 12.9 mIU/mL for the < 40 age group. The titers rose at one month to 14.3 mIU/mL and 29.0 mIU/mL for adults in the < 40 and ≥ 40 age groups, respectively.

The study demonstrated that seroconversion (≥10mIU/mL) and GMTs among older adults were low at 2 weeks after a low dose vaccine (25 U), though the sample size was small. The seroconversion rate and GMTs increased by four weeks post-vaccination.

The clinical trials and immunogenicity studies described above provide important information on hepatitis A vaccine efficacy and response. However, additional studies involving adults age > 40 years are important because hepatitis A infection can be severe in older adults. Results for discrete age ranges in older adults are also needed to better define the ages when vaccine might provide adequate post-exposure protection for HAV. However, challenges exist for conducting such studies. In geographic areas with endemic hepatitis A, most adults are immune from hepatitis A infection at an early age. In populations with low incidence of hepatitis A infection, exposures are uncommon, and a controlled efficacy trial can require years to complete a necessary sample size. For example, the trial reported from The Netherlands enrolled cases and contacts for 8 years. An attractive alternative would be to define a post-vaccination concentration of antibody to hepatitis A virus that is accepted as a correlate of protection, and determine seroconversion proportions within a time frame previously defined for prophylaxis, e.g., ≤ 2 weeks after exposure. This solicitation explores the alternative approach.

C.2. Project Objective

The Centers for Disease Control and Prevention (CDC) is seeking support from a contractor with expertise in designing and conducting clinical vaccine trials among older adults to assess the immune response to hepatitis A vaccine in accordance with possible use for post-exposure prophylaxis. The contractor, under CDC’s supervision will conduct a clinical trial with approval by the CDC and local Institutional Review Boards (IRB) and in compliance with IRB protocol. Contractors will recruit subjects, determine eligibility of subjects, obtain blood samples, perform vaccinations, monitor safety, send aliquoted blood samples to the CDC Hepatitis Reference Laboratory for analysis, inform subjects of the results or laboratory testing, and document immunogenicity according to the following objectives.

Objectives:

The primary objective is to determine the immunogenicity and safety of hepatitis A vaccination among healthy susceptible adults age ≥ 40 years by decade of life in comparison to a control group of healthy susceptible adults age 30-39 years.

Primary endpoint:

The proportion of subjects with seroconversion (total anti-HAV ≥ 20 mIU/mL)* for healthy susceptible adults age ≥ 40 years by decade of age, at pre-specified time points after administration of a single dose of hepatitis A vaccine (50U [1.0ml] VAQTA or 1,440 EL.U. [1.0ml]

HAVRIX), and pre- and post- a second (booster) dose.

*The protocol will assume that seroconversion (total anti-HAV IgG ≥ 20 mIU/mL) at 15 days post-vaccination is equivalent to protection.

Secondary endpoints:

Pre- and post-vaccination hepatitis A geometric mean titers (GMT) of total anti-HAV at pre-specified time points after administration of a single dose of hepatitis A vaccine and pre- and post- a second (booster) dose.

Safety of hepatitis A vaccine days 0-5 post-hepatitis A vaccine dose 1, and post-hepatitis A vaccine dose 2.

Benefits:

Data are lacking on the effectiveness of hepatitis A vaccine for post-exposure prophylaxis among adults 40 years and older. The results of this study will inform development of updated U.S. post-exposure prophylaxis recommendations affecting adults > 40 years of age. The current ACIP recommendations state that for persons aged > 40 years, IG is preferred; vaccine can be used if IG cannot be obtained. Hepatitis A vaccine generally is more readily available than IG for immediate use after exposure. Prophylaxis must be administered < 14 days after exposure to be effective. Hepatitis A vaccination has the advantage over IG of inducing long-term protection and potential individual benefits, such as knowledge of protection against future exposures.

C.3. Scope of Work

Independently and not as an agent of the Government, the contractor shall be required to furnish all necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government, as needed to perform the work parameters set forth in this Performance Work Statement.

The contractor shall prepare a protocol that meets the requirements of the approved Institutional Review Board (IRB) to execute a prospective, clinical trial, designed to evaluate seroprotection (anti-HAV IgG level ≥ 20 mIU/mL) and immunogenicity from hepatitis A vaccine in eligible persons. At a minimum 350 subjects will be selected from among hepatitis A susceptible applicants ages 30-39 years and ≥ 40 years (40-40, 50-59, 60-69) who meet the inclusion criteria and who do not meet the exclusion criteria for the study as specified in the protocol. The contractor shall obtain a blood sample prior to enrollment to determine study eligibility. HAV antibody titers and liver function (i.e., alanine aminotransferase [ALT]) will be assessed to exclude disease affecting the liver. Subjects who are determined ineligible, e.g., by the presence of pre-vaccination seroprotection against hepatitis A, abnormal liver function, immunocompromised, chronic illness or contraindication to vaccination, will be excluded. For eligible subjects, hepatitis A vaccine will be administered as soon as possible after eligibility is confirmed (day 0).

Blood draws will occur at days 15 and 30 days after administration of the first dose of hepatitis A vaccine;

a second dose of hepatitis A vaccine will be administered six (6) months after the first vaccine dose; blood draws will occur prior to (on the same day) as administration of the second vaccine dose and 30 days after administration of the second dose. (Exact timing is specified in section C4 1.16 and 1.17).

The contractor shall perform the liver function tests and initial anti-HAV testing (total anti-HAV) to determine subject eligibility for the first vaccine and the first study blood draw (see section C4 1.5). All blood samples with negative anti-HAV total results will be sent to the CDC Hepatitis Reference Laboratory for confirmation (Total anti-HAV) and HBV (HBsAg) and HCV (Total anti-HBc, IgM-anti HBc, Anti-HCV) serologies. When these results are available, subject eligibility to continue the study will be determined.

The CDC Hepatitis Reference Laboratory will perform all subsequent study anti-HAV serologies. Up to a total of six (6) visits and six (6) blood draws will be requested of the eligible study subjects (see proposed subject study schedule below). Standard serological assays will be utilized as specified by the CDC Hepatitis Reference Laboratory. Abnormal liver function tests will be defined based on the normal values for the assay and laboratory utilized for the study.

Investigators shall inform ineligible subjects (based on history or laboratory tests) of their individual results in writing as soon as possible after the results are known (see section C4 1.5). Investigators shall inform eligible subjects of their individual results within six (6) months of the last blood draw.

Investigators will document that both ineligible and eligible subjects have been informed of the results obtained in this study, and any referrals made for additional care.

The contractor shall be responsible for monitoring, documenting, and reporting serious adverse events of any cause within five (5) days to CDC, and the appropriate IRB, and to Vaccine Adverse Event Reporting System (VAERS) if deemed vaccine related. Investigators will, in their clinical judgment, report whether the adverse event is related to vaccination. A Safety Monitoring Report describing any serious adverse events is required five (5) working days after each quarterly conference call.

Once the contract is awarded, CDC will work with the contractor to ensure compliance with a detailed schedule including, but not limited to, blood draws, speimen storage, specimen delivery, vaccine administration, vaccination follow-up calls, medical and safety assessment, and receipt of serological results from CDC.

Proposed Subject Study Schedule:

Group Age

(years) Pre-study blood draw to determine eligibility

Day 0, blood draw #1 and vaccine #1 (blood draw prior to vaccine)*

5 day post-vaccine #1 call

15 day blood draw #2

30 day blood draw #3 months blood draw #4 + vaccine #2

5 day post-vaccine #2 call

6 months + 30 days (7) blood draw #5

Control Group

30-39 X X x x x x x x

Study Group

40-49 X X x x x x x x

Study Group

50-59 X X x x x x x x

Study Group

60-69 X X x x x x x x

*Day 0 blood draw#1 and vaccination #1 should occur as soon as possible after eligibility is determined (but no later than 15 days after pre-study blood draw) based on history and results of the contractor performed anti-HAV total and ALT even if confirmatory anti-HAV total, or HBV and HCV results are not yet known. Subjects later found to be ineligible based on anti-HAV total, HBV, or HCV results should not proceed with further blood draws or vaccination after the results are known.

Location of study:

United States. Large multi-disciplinary clinical care setting.

Duration of Study Participation/ Study Period:

Recruitment and enrollment of subjects must be accomplished in no more than six (6) months. The duration of study participation for each subject will be approximately seven (7) months: six (6) months for the first vaccine dose follow-up period and one (1) month for the second vaccine dose follow-up period. Results of blood draws will be provided to subjects within six (6) months of the last blood draw.

Follow-up analysis and manuscript writing will take place at the completion of enrollment and when results are available from blood draw #3 and again after blood draw #5. The contract duration (3 years) will allow for manuscript completion, including CDC clearance and peer-review, follow-up analysis and time to address any follow-up questions or concerns.

Contractor expenses:

The contractor shall provide all materials (e.g., vaccine), liver function tests, labor, and equipment required to complete the tasks outlined below. The contractor shall be responsible for expenses incurred by required travel or communication with CDC, and for obtaining materials needed to complete the work relevant to CDC program requirements and data acquisition. The contractor shall be responsible for any subject incentives.

C.4. Technical Requirements

The contractor shall work with and report to the CDC Division of Viral Hepatitis (DVH) Vaccine Research and Policy Team. The contractor shall perform the following activities which will be determined satisfactory when approved by the DVH team, and provide the deliverables described within the timeframes specified below:

1.1: The contractor shall write a protocol to meet the objectives of the study outlined above in collaboration with the CDC/DVH team and receive approval from CDC prior to implementation of the protocol. The protocol shall be completed within 90 days after contract award. Any requested modifications by CDC will be completed within 15 days from receipt.

1.2: Institutional Review Board (IRB) approval will be obtained prior to enrolling subjects. DVH approval/revisions and IRB submission/approval revisions are due within six (6) months after contract award.

1.3: The contractor shall develop implementation procedures for the study. Procedures must be approved by the COR and will include conducting interviews based on a standard questionnaire to determine subject eligibility, for managing data that tracks enrollment, drop-outs (with reason), vaccination information (e.g., lot number, site of administration), laboratory results (e.g., assay, site sample obtained), and subject clinical status at each visit. Standard data collection forms will be drafted by the contractor and finalized in collaboration with the CDC/DVH team. Baseline and ongoing data collection for eligible subjects will include subject demographics, medical diagnoses, medications, previous receipt or non-receipt of hepatitis A vaccine, birth country and travel history, anti-HAV IgG titers at the specified time points, and at each visit, past history of hepatitis A infection and possible sources of HAV infection (e.g., risk factors). Information on new HAV infections will be reported to state health departments in accordance with routine state reporting requirements. (See section C5 for sample data tables.)

1.4: The contractor shall develop data management tools including development of a database and data dictionary and receive CDC approval of such. The contractor shall outline procedures for and perform data entry and data cleaning throughout the study for results obtained by the contractor. The data will be delivered quarterly in CSV and XLS format (Quarterly Data Report). The contractor shall provide CDC with a copy of the final cleaned and de-identified data set (Final Data Report). The Quarterly Data Report is due on a quarterly basis on/before the 15 th of the month. The Final Data Report is due on/before the expiration date of the contract.

1.5: The contractor shall identify and recruit study subjects who meet the inclusion criteria of the study and who do not meet the exclusion criteria. Eligibility will be determined initially based on history and results of the contractor performed anti-HAV total and ALT. All eligible subjects will be vaccinated and entered into the study, even if confirmatory anti-HAV total and HBV or HCV results are not yet known.

Subjects later found to be ineligible based on anti-HAV total, HBV, or HCV results performed by CDC Hepatitis Reference Laboratory should not proceed with further blood draws or vaccination after the results are known. All data collected from these subjects and all subjects should be documented, retained, and included in progress reports. The contractor shall report on study enrollment progress at six (6), nine (9), and twelve (12) months after contract award. (Enrollment Initiation Report, Enrollment Mid- Period Report, and Enrollment Completion Report).

Inclusion Criteria:

1. Subjects aged ≥ 40 years from four comparably sized groups, 40-49; 50-59; 60-69 years; and a control group of subjects ages 30-39 years.

2. Written informed consent.

3. Free of obvious health problems that may interfere with vaccine immunogenicity or safety as established by medical history including physical examination and the clinical judgment of the investigator in conjunction with CDC. (See section 1.8 below)

4. Subject is willing and capable of returning for follow-up visits and of undergoing peripheral venous blood draws.

Exclusion Criteria:

The 2007 ACIP recommendations specify that immune globulin should be used for post-exposure prophylaxis for immunocompromised persons, persons who have had chronic liver disease diagnosed, and persons for whom vaccine is contraindicated. Potential unvaccinated subjects in these categories should be considered ineligible for the study. Specific exclusion criteria follow:

1. Persons who report or have records of receipt of any dose of hepatitis A vaccine and/or diagnosis of hepatitis A.

2. Persons confirmed seropositive for anti-HAV total at a pre-study visit or day 0 (i.e., current or prior HAV infection; received the hepatitis A vaccine).

3. Subjects for whom vaccine is contraindicated (i.e., subjects with known hypersensitivity to any component of the hepatitis A vaccine.)

4. Subjects with known or suspected liver disease (acute or chronic, including hepatitis B or hepatitis C); moderate or severe chronic illness.

5. Subjects with abnormal liver function tests. [Note: abnormal will be defined based on the normal values for the assay and laboratory utilized for the study]

6. Known exposure to hepatitis A in the past 60 days.

7. Administration of another vaccine (other than influenza vaccine) within 30 days prior to administration of study vaccine or planned vaccination during the study (i.e., no concomitant vaccines except for influenza.)

8. Administration of immunoglobulin and/or blood products within 90 days prior to the administration of the study vaccine.

9. Subjects with immunocompromising conditions, including chronic administration of immunosuppressive agents (> 14 days) or immune-modifying agents within 90 days prior to the study start (including systemic steroids ≥ 20mg/day.)

10. Acute illness at the time of vaccination.

11. Acute or chronic disease determined by history that might interfere with the study objectives in the opinion of the investigator.

12. Pregnancy or intention.

13. Inclusion of more than two (2) family members in the study.

14. Subject born in a hepatitis A endemic area or travels frequently to a hepatitis A endemic area.

1.6: The contractor will recruit sufficient subjects within six (6) months of study initiation, such that the sample size for the study groups and controls is adequate to demonstrate a statistically significant effect with consideration of loss to follow-up. The endpoints are percent seroconversion by age group and GMTs at day 15, 30 and six (6) months after the first vaccination and 30 days after the second vaccination.

Sample size estimates should be based on study completion per protocol. All sample size estimates and enrollment limits must be reviewed by and discussed with CDC/DVH. The minimum sample size for each age group is 100 and for the control group is 50. (See section C4 1.5 for inclusion/exclusion criteria).

Example:

N (ages 30- 39)

% seroconverted at 15 days (control)

N (ages 40+.

i.e., 40-49, 50-59, 60-69)

% seroconverted at 15 days (age 40+)

Sig level Power

50 0.95 50 0.78 0.05 0.8

75 0.90 75 0.75 0.05 0.8

150 0.90 150 0.80 0.05 0.8

100 0.95 100 0.78 0.05 0.8

50 0.90 75 0.80 0.05 0.8

50 0.90 100 0.80 0.05 0.8

50 0.90 125 0.75 0.05 0.8

50 0.80 150 0.90 0.05 0.8

1.7: Subjects enrolled in the study can be offered an incentive and/or reimbursement for expenses at the discretion of the contractor.

1.8: The contractor shall conduct all study activities in accordance with the provisions of local IRB review/approved protocols and under the direction of CDC. The contractor shall obtain written informed consent for additional follow-up and/or additional viral hepatitis studies conducted at CDC from remaining samples in accordance with IRB approved protocols. The consent will specify that the samples may be used for genetic studies related to viral hepatitis, and that the samples may be stored for up to 10 years.

1.9: The contractor shall follow direction from the CDC Hepatitis Reference Laboratory to create procedures for assigning unique identifiers, access to codes for unique identifiers, and management of confidential records. The identifiers and a suffix pertaining to each blood draw will be determined and used by the CDC Hepatitis Reference Laboratory for label production. The contractor will prepare unique codes linking case information and samples to prevent CDC from obtaining case identifiers. Subject information containing identifiers will not be shared with CDC. Master lists linking unique codes and case information will be destroyed by the contractor after the results of the study are published.

1.10: The contractor shall conduct a medical and safety assessment for all subjects prior to study entry and for a defined period after each dose of vaccine. Additional monitoring will be done by the contractor to identify adverse events during the course of the study. The medical and safety assessment will include taking a medical and vaccination history at the start of the study. The medical history will include diagnoses, medications, past or present hepatitis virus infection (e.g. serology for HAV, HBV, HCV), chronic liver disease, heart disease, kidney disease, and diabetes. At each visit, changes to the medical history, including new diagnoses and medications should be requested. Assessing local and systemic reactions, medications taken, adverse reactions and serious adverse reactions will be documented throughout the study. Phone calls with subjects five (5) days after each vaccination will inquire about adverse effects of the vaccine or blood draw. Diary cards will be used and all adverse events will be followed to resolution.

The contractor shall report all adverse events to CDC within five (5) days, to the regulating IRB in accordance with local requirements, and to VAERS when/if adverse events are judged by the investigators to be possibly vaccine related. A Safety Monitoring Report describing any serious adverse events is required five (5) working days after each quarterly conference call.

1.11: The contractor shall be responsible for the purchase and acquisition of hepatitis A vaccine from one manufacturer (HAVRIX, Smith-Kline Beecham Biologicals, Rixensart, Belgium OR VAQTA, Merck & Co., Inc, Whitehouse Station, NJ). Vaccine from the same one or two lots from the same manufacturer will be used throughout the study for all participants. Using vaccine from two different manufacturers is strictly prohibited. Vaccine will be administered intramuscularly in the deltoid area (1mL adult dose of vaccine containing 1440 EL.U. antigen for HAVRIX, or 1.0 mL adult dose containing 50 Units antigen for VAQTA).

1.12: The contractor shall conduct and oversee hepatitis A vaccination for all subjects meeting the inclusion criteria for the study, on day 0 (first dose) and six (6) months (second dose) and document the date of vaccination, type of vaccine, manufacturer, site and route of administration, dose, lot number, and expiration date. The contractor shall track vaccine vials and lot numbers of vaccine administered during the study.

1.13: The contractor shall assess all subjects for signs/symptoms of hepatitis A during the course of the study. Subjects will be asked to report known exposures to hepatitis A virus or disease during the study period. Any laboratory confirmed hepatitis A cases must be clearly documented with the appropriate laboratory testing and excluded from further study participation.

1.14: The contractor shall conduct and oversee blood draws pre-study, day 0 (post-vaccination #1), day 15, day 30, six (6) months, and post-vaccination dose two (2) at seven (7) months. The pre-study blood draw will be used to determine anti-HAV total negativity, baseline B, C serology, and liver function tests (e.g., ALT). The contractor shall perform the anti-HAV total and ALT pre-study eligibility testing. Aliquots of the blood sample from anti-HAV total negative subjects will then be sent to the CDC Hepatitis Reference Laboratory for further serology testing. (See C4 1.16 for specifics of aliquot size, shipping and storage.)

At day 0 (prior to vaccination #1) blood should be drawn for anti-HAV IgM and IgG (blood draw #1). This should occur within 15 days after the pre-study testing results are known and on the same day and prior to vaccination #1. If blood draw #1 occurs > 15 days after the pre-study blood draw are known, repeat the hepatitis serologies for subjects considered at risk for infection.

The 15 and 30 day blood draws (#2 and #3) will determine antibody titers and seroconversion after the first vaccine dose. The six (6) month blood draw (#4) will be performed prior to dose two (2) of the hepatitis A vaccine and will serve as the baseline titer for assessing response to the second dose 30 days later.

Baseline demographic information and serology (pre-study, only) Contractor performs initial anti-HAV liver function tests CDC Hepatitis Reference Laboratory performs serologies

Subject

ID

Age Sex Race/ Ethnicity

Country of birth

Weight (lbs)

ALT HBsAg Total anti- HBc

IgM-anti HBc

Anti-

HCV

Anti-

HAV

total

Study labs (blood draws 1-5) Performed by CDC Hepatitis Reference Laboratory

Anti-

HAV

IgM

Anti-HAV total (for each blood draw 1-5)

Anti-HAV IgG (for each blood draw 1-5)

Anti-HAV IgM (for blood draw 1-2 only)

Titer (for blood draws 1-5)

1.15: The contractor shall ensure that blood draws occur within the specified time frame. Blood draw #2 must occur within three (3) days of the specified time frame (e.g., the day 15 blood draw must occur within day 12-18). The second vaccination must occur no earlier than four (4) days prior to six (6) months (i.e. vaccine administered > 4 days prior to six (6) months would be considered invalid and should be repeated six (6) months later.) Follow-up post-vaccination phone calls to document adverse events should occur within one (1) day of the specified time frame for each vaccine dose. The proposed timing of blood draws and vaccination for all blood draws and vaccinations are in the table below. All blood draws and vaccinations must be recorded exactly by date, time, and number. Any days past the acceptable range must also be documented. A Conduction of Study Report, documenting the completion of all vaccination and blood draws is due within 19 months after contract award.

Proposed timing of blood draws and vaccination:

Vaccination and blood draw

Time due Acceptable range prior to time due

Acceptable range after time due

Pre-study eligibility Blood draw

As soon as possible after subject identified

N/A N/A

Notify subject of eligibility/ ineligibility

Within 15 days after pre-study blood draw

N/A None

Vaccination #1 and blood draw #1

As soon as possible after eligibility is determined after pre-study blood draw (no later than 15 days after pre-study blood draw)*

N/A None

Blood draw #2 On day 15 post-vaccination #1

14 days post-vaccination #1

16-18 days post-vaccination #1

Blood draw #3 On day 30 post-vaccination #1

27-29 days post-vaccination #1

31-33 days post-vaccination #1

Blood draw #4 Same day as vaccination #2 (prior to vaccine)

≤ 3 days prior to vaccination #2

None; document blood draws occurring after vaccination

Vaccination #2 6 months after the 1 st dose

≤ 4 days prior to 6 months

As soon as subject is available

Blood draw #5 30 days post-vaccination #2

27-29 days post-vaccination #2

31-33 days post-vaccination #2

*Blood draw #1 and vaccination #1 should occur as soon as possible after eligibility is determined, based on history and results of the contractor performed anti-HAV total and ALT, even if confirmatory anti-HAV total or HBV or HCV results are not yet known.

Subjects later found to be ineligible based on anti-HAV total, HBV, or HCV results should not proceed with further blood draws or vaccination after the results are known.

1.16: The contractor shall obtain peripheral venous blood samples each containing a minimum of 10 mL of whole blood, and separate blood into 1.5 mL aliquots of serum. The CDC Hepatitis Reference Laboratory will perform the serological testing for all viral hepatitis A antibody titers. The aliquots should be sent to the CDC Hepatitis Reference Laboratory for determination of anti-HAV total for eligibility (pre-study), and anti-HAV total, anti-HAV IgG, and anti-HAV IgM for the subsequent blood draws following evidence based protocols. The contactor shall follow the CDC Hepatitis Reference Molecular/Serology Sample Handling and Shipping instructions for proper labeling, storage, and transport of blood samples to CDC available at: http://www.cdc.gov/hepatitis/HEV/PDFs/HRL_PCRSampleHndlgShpg_20080615.pdf Specimen labels and shipping supplies will be provided by CDC for samples to be tested by the CDC Hepatitis Reference Laboratory. Per section 1.10, labels will have a unique number; the contractor shall maintain a copy of each label in the relevant subject’s record to assure samples are accurately attributed to subjects. Aliquoted samples will be stored at -70 o C until sent by overnight mail to CDC according to the specifications in the above referenced .pdf file. All vials should be discarded at a specified time frame after study completion according to IRB policy and in accordance with the subject’s consent.

1.17: The contractor shall be responsible for communicating with the CDC Hepatitis Reference Laboratory to obtain the serology results. The contractor shall be responsible for reporting new hepatitis A virus infections to state health departments in accordance with state reporting requirements. The contractor shall be responsible for providing the subjects with the results in writing of CDC Hepatitis Reference Laboratory testing.

1.18: Investigators shall document that both ineligible and eligible subjects have been informed of the results obtained in this study and any referrals made for additional care.

1.19: Analyses will be conducted jointly between the contractor and CDC/DVH. At a minimum, the analysis will include plots of the HAV seroconversion results by age and geometric mean antibody titers;

univariate analysis will include a summary of the risk factors, demographic information and other key factors included in the standard questionnaire.

1.20: The contractor shall work with CDC/DVH to prepare and present the analyzed data in a national forum.

1.21: The contractor shall be responsible for providing CDC with a monthly progress report as outlined in section C.5.

1.22: The contractor shall participate in meetings or teleconferences with the CDC technical monitor and other CDC/DVH team members. Calls will occur at the discretion of CDC at least weekly in order to finalize implementation protocols at regular intervals (TBD) thereafter.

1.23: The contractor shall participate in meetings or teleconferences with the CDC technical monitor and other CDC/DVH team members to monitor progress of the study at the direction of CDC. Calls and meetings will occur no less than once every quarter. The contractor shall provide a written summary of the study progress for discussion at each meeting (Quarterly Conference Report). The report should include a summary of the previous teleconference, significant accomplishments during the reporting period, problem areas and recommendations for solution, activities planned for the next quarter, and special items of interest and activity. In addition, the report should include a table of subjects enrolled in each arm, subjects not eligible, subject lost to follow-up or withdrawing from the study, adverse events requiring reporting, and blood draws out of protocol (i.e., outside of the range specified in 1.16 above).

Such quarterly conference reports should be submitted to CDC no less than five (5) days prior to a meeting/teleconference. The quarterly conference reports should be updated based on the meeting/teleconference within five (5) days after the meeting and delivered to CDC.

1.24: The contractor shall aid in the preparation of two manuscripts, 1) short term response by age group; 2) overall response after the second vaccine dose by age group, for submission to a peer-reviewed journal with CDC co-authors within 30 months after contract award. The contractor shall make revisions to the manuscript as suggested by CDC before and during CDC clearance. The contractor shall submit the http://www.cdc.gov/hepatitis/HEV/PDFs/HRL_PCRSampleHndlgShpg_20080615.pdf

CDC cleared manuscript to a peer reviewed journal and continue to revise the manuscript in collaboration with CDC as required for publication. The contractor shall be responsible for any fees associated with publication.

1.25: The contractor shall obtain CDC approval for any deviation from the CDC-approved study protocol.

1.26: The contractor shall prepare and perform a site visit in collaboration with CDC personnel.

1.27: The contractor shall describe any partners and/or subcontractors and their expertise for any partners and/or subcontractor whose services were utilized in this study.

1.28: The contractor shall schedule an initial kick-off meeting with CDC and present the preliminary study plan. The kick-off meeting must take place within two (2) weeks after contract award. A Kick-Off Meeting Report is due within one (1) week after the kick-off meeting. The Kick-off meeting report is due three (3) weeks after contract award.

1.29: The contractor shall provide a final report (Final Progress Report) at the completion of the study, including compilation of all activities involved in the study.

1.30: The contractor shall provide a Technical Research Documentation Report, documenting all aspects of the research study, including the study methods, protocols for recruitment, implementation, and includes, but is not limited to, all relevant forms, data dictionaries, IRB submissions, study methods, and protocols. The final format will be provided to the contractor by CDC/DVH upon award of the contract.

The final technical research documentation report is due on/before the expiration date of the contract.

C.5. Reporting Requirements

In addition to those reports required by other terms of this contract, the contractor shall submit to the Contracting Officer (CO) and the Contracting Officer’s Representative (COR) progress reports. These reports will require descriptive information about the activities undertaken during the reporting period and will require information about planned activities for future reporting periods.

C.5.1. Monthly Progress Reports

Ten (10) days after the end of each month, the contractor shall submit a monthly progress report to the CO and the COR. The form, format, and content of the monthly progress reports will be coordinated between the contractor and the COR on an onging basis. Such reports shall include the following information:

- enrollment status (see sample table below)

- demographic and baseline information of the enrolled subjects (see sample table below)

- blood samples collected

- blood samples shipped to CDC

- adverse events documentation and reporting verification

Example of tables that should be updated and included in all…