Protocol 028

OUTLINE OF PROTOCOL 028

A PHASE I SAFETY AND IMMUNOGENICITY TRIAL OF ORALLY ADMINISTERED LIVE ATTENUATED RECOMBINANT SALMONELLA TYPHI CVD 908 asd (pW57-asd+) EXPRESSING HIV-1 LAI gp120 (VVG 203) AND PARENTERALLY ADMINISTERED HIV-1 MN RGP120 IN ALUM IN HIV-1-UNINFECTED VOLUNTEERS

Subjects: Healthy, HIV-1 uninfected adult volunteers 18-50 years old who have no identifiable high-risk behavior for HIV-1 infection. [Number of Subjects = 47]

Schema:

Part I 20 Subjects	Group A volunteers will be followed for at least 21 days before initiation of enrollment into Group B Group B volunteers will then be assessed for safety for a minimum of 21 days prior to initiation of Part II
VOLUNTEERS		IMMUNIZATION (Month 0 only)
Group	Number	VVG Dose	Route
A	10	5x10⁵ cfu	Oral
B	10	5x10⁶ cfu	Oral
Total	20
VVG: Dose expressed in colony forming units (cfu) of Salmonella typhi CVD 908-HIV-1 LAI gp120 (VVG 203) with bicarbonate buffer (oral inoculation).

Part II
27 subjects

VOLUNTEERS

VACCINATION SCHEDULE AND
ROUTE OF ADMINISTRATION

Group

Active/

Control^**

Total Number

Months

0

2

6

C

8/1

9

VVG (Oral)

MN (IM)

MN (IM)

D

8/1

9

VVG (Oral)

VVG (Oral)

VVG (Oral)

E

8/1

9

MN (IM)

MN (IM)

VVG (Oral)

Total

24/3

27

Route of Administration:

VVG: 5 x 10⁷ colony forming units (cfu) of Salmonella typhi CVD 908-HIV-1 LAI gp120 (VVG 203) with bicarbonate buffer (oral inoculation)

MN: VaxGen MN rgp120/HIV-1 (300 µg) in alum, given by the IM route

** At each immunization, control volunteers will receive sodium bicarbonate (NaHCO₃) buffer instead of VVG 203 (oral inoculation) or Alum Placebo instead of MN rgp120 (IM injection)

ACCRUAL AND IMMUNIZATIONS COMPLETED

Product Description:

Attenuated S. Typhi CVD 908 as a live vector expressing an engineered prokaryotic expression cassette that encodes HIV-1 gp120 or truncated gp120, resulting in secretion of rgp120 into the cytoplasm or periplasmic compartment of the S. Typhi vector. [University of Maryland Center for Vaccine Development]
MN rgp120: CHO cell-derived MN rgp120 combined with alum [VaxGen]

Time Period: 12 months with the possibility of extension; first volunteer enrolled on 12/05/97 and the last on 05/18/99.

Clinical Site: Johns Hopkins University Center for Immunization Research (JHU CIR)

Study Chair: David Schwartz, Johns Hopkins University

INCLUSION CRITERIA

Standard inclusion criteria, with the addition of:

Viable EBV line at time of enrollment

EXCLUSION CRITERIA

Standard exclusion criteria, with the addition of:

History of migraine or recurrent severe headaches
History of cardiac valve defects or congenital heart disease
History of gastrectomy, gallstones or gallbladder disease
Allergy to ciprofloxacin or trimethoprim-sulfamethoxazole
History of typhoid fever or previous immunization against typhoid fever
Household contact with children under two years of age or persons who are pregnant, immunocompromised or infected with HIV-1
Work as food handler, or in health care or day care setting
Use of antibiotics, antacids or H2 blockers within 7 days of oral immunization
NOTE: Volunteers who are using these agents at time of screening and meet all other eligibility criteria, may be enrolled after cessation of use for a minimum of 7 days.
Positive serum p24 antigen test within 7 days prior to initial oral immunization
Allergy to thimerosal

STUDY GOALS

To evaluate the safety of VVG 203 in a dose escalation vaccine regimen of 5x10⁵ cfu given alone, 5x10⁶ cfu given alone, and then 5x10⁷ cfu of VVG 203 given alone or sequentially with HIV-1 MN rgp120 by:
- determining the incidence of fever and other symptoms after vaccination with VVG 203
- determining the frequency of recombinant S. typhi CVD 908-gp120 (VVG 203) organisms transiently present in blood (vaccine bacteremia) and the quantity of vaccine organisms excreted in stool.
To evaluate the systemic humoral and cellular immune responses as well as mucosal immune responses to 5x10⁵ and 5x10⁶ cfu of VVG 203 alone; immune responses to be characterized include:
- serum binding antibodies to HIV-1 IIIB and MN V3 peptides and HIV-1 IIIB rgp120 and HIV-1 MN rgp120, and H and O antigens of S. typhi
- neutralizing antibodies to the IIIB isolate of HIV-1
- ELISPOT to detect B cells secreting IgA, IgG and IgM antibodies to S. typhi O and H antigens, to HIV-1 MN rgp120, and to HIV-1 IIIB rgp120 (if sufficient specimen is available)
- secretory IgA antibodies to HIV-1 MN rgp120, HIV-1 IIIB rgp120 (if sufficient specimen is available), and to O and H (flagellar) antigens of S. typhi in parotid saliva, stool, and genital (vaginal or seminal) fluids
- lymphoproliferation to HIV-1 IIIB rgp120 and to LPS and H antigens of S. typhi
- CD8+ and CD4+ cytotoxic T lymphocyte (CTL) activity specific for HIV-1 envelope
- cytokine secretion in response to HIV-1 IIIB rgp120 and/or HIV-1 MN rgp120 and to H antigen of S. typhi
- resistance to HIV-1 in vitro challenge
To evaluate the systemic humoral and cellular immune responses as well as mucosal immune responses resulting from priming and boosting with 5x10⁷ cfu of attenuated Salmonella typhi CVD 908-gp120 recombinant (VVG 203) vaccine and boosting with the VVG 203 alone or with HIV-1 MN rgp120; immune responses to be characterized will include:
- neutralizing antibodies to the IIIB and MN isolates of HIV-1
- cross-neutralizing antibodies to other isolates of HIV-1, if homologous neutralizing antibodies are detected
- serum binding antibodies to HIV-1 IIIB and MN V3 peptides, HIV-1 IIIB rgp120, HIV-1 MN rgp120, and H and O antigens of S. typhi.
- ELISPOT to detect B cells secreting IgA, IgG and IgM antibodies to S. typhi O and H, HIV-1 MN rgp120 and HIV-1 IIIB rgp120 (if sufficient specimen is available)
- secretory IgA antibodies to HIV-1 MN rgp120 and S. typhi O and H antigen in parotid saliva, stool, and genital (vaginal or seminal) fluids.
- lymphoproliferation to HIV-1 IIIB rgp120, MN rgp120 and to the LPS and H (flagellar) antigens of S. typhi (indicative of immunological memory)
- CD8+ and CD4+ cytotoxic T lymphocyte (CTL) activity specific for HIV-1 envelope.

Part II 27 subjects
VOLUNTEERS			VACCINATION SCHEDULE AND ROUTE OF ADMINISTRATION
Group	Active/ Control^**	Total Number	Months
			0	2	6
C	8/1	9	VVG (Oral)	MN (IM)	MN (IM)
D	8/1	9	VVG (Oral)	VVG (Oral)	VVG (Oral)
E	8/1	9	MN (IM)	MN (IM)	VVG (Oral)
Total	24/3	27
Route of Administration:		VVG: 5 x 10⁷ colony forming units (cfu) of Salmonella typhi CVD 908-HIV-1 LAI gp120 (VVG 203) with bicarbonate buffer (oral inoculation) MN: VaxGen MN rgp120/HIV-1 (300 µg) in alum, given by the IM route
** At each immunization, control volunteers will receive sodium bicarbonate (NaHCO₃) buffer instead of VVG 203 (oral inoculation) or Alum Placebo instead of MN rgp120 (IM injection)