Comparison of acellular and whole-cell pertussis-component diphtheria-tetanuspertussis vaccines in infants Dean A. Blumberg, MD, ChrisAnna M. Mink, MD,* James D. Cherry, MD, MSc, Candice Johnson, MD, PDD,Rachel Garber, MD, Stanley A. Plotkin, MD, Barbara Watson, MD, Gerard A. Ballanco, MD, Robert S. Daum, MD,* Bradley Sullivan, MD, Timothy R. Townsend, MD, James Brayton, MD, W. M. Gooch III, MD, David B. Nelson, MD, Blaise L. Congeni, MD, Charles G, Prober, MD, Jill G. Hackell, MD, Cornelia L, Dekker, MD,* Peter D. Christenson, PhD, and the APDT Vaccine Study Group** From the Departments of Pediatrics and Biomathematics, School of Medicine, University of California, Los Angeles; MetroHealth Medical Center and Rainbow Babies and Childrens Hospital, Cleveland, Ohio; the Division of Infectious Diseases, Children's Hospital of Phi/adelphia, Philadelphia, Pennsylvania; Rothschild Pediatric Group, Metairie, Louisiana; Pediatric Infectious Diseases, Tulane University School of Medicine, New Orleans, Louisiana; Marshfield Clinic, Marshfield, Wisconsin; Johns Hopkins Hospital, Baltimore, Maryland; Clinical Pharmacology, Primary Children's Medical Center, Salt Lake City, Utah; Department of Pediatrics, Children's Hospital of Wisconsin, Milwaukee; Children's Hospital Medical Center, Akron, Ohio; Department of Pediatrics, Stanford University Medical Center Palo Alto, California; Lederle Biologicals, Pearl River, New York
In a multicenter, double-blind, randomized, longitudinal study, 252 children received licensed Lederle diphtheria-tetanus toxolds and pertussis vaccine adsorbed (DTP) at 2, 4, and 6 months of age, and 245 children received a DTP vaccine with the Lederle/Takeda acellular pertussis component (APDT) at the same ages. Both groups of children received APDT vaccine at 18 months of age. After each of the first three immunizations, APDT vaccine recipients had fewer local and systemic reactions than did DTP vaccinees. Reactions after the 18-month APDT vaccination were minimal in severity regardless of the vaccine previously received. Antibody responses to lymphocytosis-promoting factor and agglutinogens were more pronounced in DTP recipients; however, APDT recipients had a better serologic response to filamentous hemagglutinin, and responses to the 69K protein were equivalent. This APDT vaccine produces fewer reactions than the standard whole-cell DTP vaccine. The protective significance of the serologic responses to the APDT vaccine is unknown, but the greater response to filamentous hemagglutinin and equivalent response to the 69K protein c o m p a r e d with those to DTP vaccine seem promising. (J PEDIATR1991;119:194204) Presented in part at the Fifth International Symposium on Pertussis, Copenhagen, Denmark, Sept. 22, 1988; the joint meeting of the American Pediatric Society and the Society for Pediatric Research, Washington, D.C., April 29, 1989; and the International Symposium on Pertussis: Evaluation and Research on Acellular Pertussis Vaccines, in Shizuoka, Japan, Sept. 14, 1990. (In relation to these meetings, published in part: Tokai J Exp Clin Med 1988;13:21-28 and Pediatr Res 1989;25:175A.) Submitted for publication Nov. 19, 1990; accepted Feb. 8, 1991. Reprint requests: James D. Cherry, MD, Department of Pediatrics,
194
University of California at Los Angeles School of Medicine, Los Angeles, CA 90024-1752. *Dr. Mink is now at the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Washington, D.C.; Dr. Daum is at the University of Chicago School of Medicine, Chicago, Ill.; and Dr. Dekker is at Chiron Corp., Emeryville, Calif. **See Addendum for list of other members of the APDT Vaccine Study Group. 9/20/28583
Volumell9 Number2
APDT DTP ELISA EU FHA LPF
Compar~onofAPDT and DTP vaccines
Acellular pertussis-component DTP vaccine Diphtheria and tetanus toxoids and whole-cell pertussis-component vaccine, adsorbed Enzyme-linked immunosorbent assay ELISA unit Filamentous hemagglutinin Lymphocytosis-promoting factor
Currently licensed pertussis vaccines are associated with many reactions, 1,2 and development of a less reactogenic vaccine is desirable. In Japan, several acellular pertussiscomponent vaccines have been developed and used for routine immunization, a, 4 These vaccines produce minimal side effects, and their use is controlling epidemic pertussis in Japan. One Japanese acellular-component vaccine, manufactured by Takeda Chemical Industries, Osaka, Japan, was formulated into an APDT vaccine with diphtheria and tetanus toxoids prepared by Wyeth Laboratories, Philadelphia, Pa., and testing in the United States revealed few side effects. 510 More recently the Takeda acellular pertussis Component has been combined with Lederie Laboratories (Pearl River, N.Y.) diphtheria and tetanus toxoids. Members of our group previously compared Lederle/Takeda APDT vaccine with Lederle DTP vaccine administered as the fifth DTP immunization to 4- to 6-year-old children 11 and as the fourth DTP immunization administered to 17- to 24-month-old ehildrenl2; this APDT vaccine was immunogenic and less reactogenic than the whole-cell pertussiscomponent DTP vaccine. In this article the results of a multicenter randomized longitudinal double-blind study are reported in which Lederle/Takeda APDT vaccine was compared with Lederle DTP vaccine administered to 2-, 4-, and 6-month-old infants, with all subjects receiving APDT vaccine at 18 months of age. METHODS Subjects. Four-hundred ninety-seven healthy 2-monthold infants were enrolled at 10 study sites. In a double-blind manner, 252 children were randomly selected to receive DTP vaccine at 2, 4, and 6 months of age, and 245 children were randomly selected to receive APDT vaccine at the same ages. All children were scheduled to receive APDT vaccine at 18 months of age. Vaccine was administered in a volume of 0.5 ml into the anterior lateral thigh muscle through a 1-inch 25-gauge needle. The parents were requested to maintain a diary of local and systemic reactions for 10 days after immunization. Rectal temperature was recorded before immunization and 30 minutes and 3, 6, 24, 48, and 72 hours after immunization. The presence or absence of the following reactions was recorded at 30 minutes and at 3 and 6 hours after vaccination and daily thereafter for 10 days: local tenderness, vesicles, erythema, induration, swelling, and elevated site temperature; drowsiness, irrita-
195
bility, vomiting, and persistent or unusual crying. Antipyretic medication wa s not routinely administered but was recommended for rectal temperature -->39~ C. Reactogenicity and antipyretic administration data were obtained by telephone contact 1, 2, 3, and 14 days after each immunization. Medical office visits for infections and all hospitalizations were recorded between the 7-month follow-up visit and the 18-month APDT immunization. This study was approved by the institutional review boards at each institution. Informed consent was obtained from the parents or guardians after the design and purpose of the study were explained. Subject enrollment began May 1987, and the last subject completed the 19-month follow-up visit July 1989. Laboratory techniques. Serum samples were obtained by venipuncture for antibody measurements at 2 months (before the first immunization), 6 months (before the third immunization), 7 months, 18 months (before the fourth immunization), and 19 months of age. Because of insufficient serum volume, not all antibody values were determined for all children. Specific immunologic responses were assayed at Lederle Biologicals. An enzyme-linked immunosorbent assay was used to determine lymphocytosis-promoting factor and filamentous hemagglutinin antibody values, 13 and 69K protein antibodies were determined by ELISA as previously described) 2 At 2, 6, and 7 months of age, 69K protein antibody values were determined for subjects at only 2 of the 10 study sites. A microagglutination assay measured pertussis agglutinating antibodies using equal quantities of Bordetella pertussis strains 130 and 138 as the antigens. 13 Neutralizing antibodies to LPF were determined by the Chinese hamster ovary cell assay) 4 Antitoxin values for diphtheria were determined by the micro cell culture method using Vero cells, 15 and tetanus antitoxin values were determined by neutralization in mice. 16 Antibody values were excluded from analysis for subjects who were vaccinated outside of acceptable age intervals or who had blood drawn outside of acceptable postimmunization intervals. Acceptable age intervals for vaccination were defined as (number of subjects excluded in parentheses): dose 1, from 6 weeks to 3 months of age (5 subjects); dose 2, from 3.5 to 6 months and >6 weeks since first dose (32); dose 3, from 5 to 8 months and >6 weeks since second dose (48); and dose 4, from 15 to 21 months (6). The acceptable postimmunization interval was 3 to 9 weeks after the third dose for the 7-month blood draw (20 subjects), and after the fourth dose for the 19-month blood draw (27). Vaccines. The DTP vaccine was a single lot of commercially available licensed Lederle adsorbed vaccine (Tri-Immunol) containing 12.5 Lf of diphtheria toxoid and 5 Lf units of tetanus toxoid per dose, and the pertussis compo-
196
Table
Blurnberg et al.
The Journal of Pediatrics August 1991
I. F r e q u e n c y o f local and s y s t e m i c reactions within t h e first 72 hours after i m m u n i z a t i o n Dose I at 2 m o DTP (n = 252)
Dose 2 at 4 m o
APDT (n = 245)
DTP (n = 241)
APDT (n = 230)
Dose 3 al 6 m o DTP (n = 231)
Dose 4 at 18 m o
APDT (n = 223)
APDT (n = 397")
Local reactions Tenderness Erythema Any >20 mm Induration Any >20 mm Swelling >10 mm Site Temperature Warm or hot Hot Vesicles
48.1
8.6~"
27.8
4.8?
25.1
5.4?
18.3
44.1 8.3
22.9"~ 0t
44.4 7.9
28.3t 3.0:~
43.3 3,5
25,1 + 2,7
26.6 11.3
42.1 10,3 21,8
7.81" 1.2t 4.9~"
37.3 8.3 14.9
15.2t 0.9t 8,2~
37,7 4.3 15.1
16,6? 1.8 7.2~:
23,6 7.5 14.2
35.3 1.6 0.4
9.0~ 0.4 0
24,1 3.7 0.8
8,7t OCT 0
23.8 1.3 0.9
4.9~" 0 0
13,3 2.3 0,3
37.7 1.6
4.5t 1.2
34,0 3.3
9.1t 0~
39.7 6,5
14.8t" 1.4~+
21.2 2.8
38.9 7.5
19.2r 0.8t
38.6 1.2
l 7.8r 0.9
41.1 3.5
23.2"~ 0.9
15, l 0.8
31.0 7.1 5.2 5.6 4,0 0
17,61" 1.6~ 3.7 1.2:t: 0~ 0
l 9,9 1.7 4.6 3.3 0.8 0
12.6,~ 1.3 3.0 1,3 0 0
22.3 1,8 4.8 0.9 0 0.4
10,01" 0.9 0.9~ 0.9 1.4 0.4
2.8 0.3 1.5 0.3 0.3 0
Systemic reactions Rectal Temperature _>38.0 ~ C >_39.0 ~ C Irritability Any Markedw Drowsiness Any Marked Vomiting Persistent crying Unusual crying Hypotonic-hyporesponsive episode Seizures
0
0
0
0
0
0
0
Values are percentage of children vaccinated experiencing designated event. "199 subjects from the initial DTP group and I98 subjects from the initial APDT group. Sp ~0.001 DTP versus APDT. Sp 40.5 ~ C Other TOTAL
DTP group
APDT group
19 10 7 4
19 1l 7 3
1
2
7 1 1 3* 53
1 1 0 35 47
*One subject each with failure to thrive, development of immunodeficiency disorder, and death. tOne subject with difficulty obtaining blood samples and two subjects with frequent illnesses.
Volume 119 Number 2
Ld (/3
Comparison o f A P D T and DTP vaccines
250
LPF(=16 T LPF(=16 /
Q----oAPDT: P r e - l m m *--* DTP: P r e - l m m
o - - - - o A P D T : P r e - l r n m LPF)16 =--= DTP: P r e - l m m LPF>16
+1
#
I--
o----oAPDT: P r e - l m m o--. DTP: P r e - l m m
CH0(=32 CH0(=32
o-----oAPDT: P r e - l m m =--= DTP: P r e - l m m
CH0)32 CH0)32
1200-
g 150
LO r
1600
+1
200
c ,< U3
Ld 03
19 7
.s +~
800-
~O
400-
100 -
L) "C_
5(3-
E
o (D C9
~ 2
6
7 Months
APDT N: DTP N:
Pre-lmm
LPF (=16 Pre-lmm LPF )16
APDT N: DTP N:
107 111 126 128
84 83 102 100
18
19
72 71 83 82
68 66 77 73
83 79 96 96
2
6
7 Months
Pre-lmm CHO (=32
APDT N: DTP N:
Pre-lmm
APDTN:
DTP N:
CHO )32
112 124 96 92
80 60 66 64
18
19
57 65 47 44
56 61 42 43
of age
77 88 61 58
B
A Ld 6O §
0
of age
125 o----oAPDT: P r e - l m m e--e DTP: P r e - l m m
FHA(=8 FHA(=8
n -oAPDT: P r e - l m m FHA>8 ,--m DTP: Pre Irnm FHA>8
o----oAPDT: P r e - t m m A g g l ( = 8 9 --* DTP: P r e - l r n m A g g l ( = 8
+1
o-----oAPDT: P r e - l m m A g g l ) 8 =--. DTP: P r e - l m m A g g l ) 8
150
100 -
C < (/3 LO
g 9
,\ ..\
,//"
25-
/"t
/ /'//~
\, ',\
c 100
o "u_
/ /" i~ /'i/--/t
\"\
.//-
/
//'
/" ~k I/I.-i/~'\
50
"oc
N E
/
//{k,
75-
E o co
50
/ /
2
o_
o 9 (.D
Qs 2
6
7 Months
Pre-lmm FHA
In a multicenter, double-blind, randomized, longitudinal study, 252 children received licensed Lederle diphtheria-tetanus toxolds and pertussis vaccine adsorbed (DTP) at 2, 4, and 6 months of age, and 245 children received a DTP vaccine with the Lederle/Takeda acellular pertussis component (APDT) at the same ages. Both groups of children received APDT vaccine at 18 months of age. After each of the first three immunizations, APDT vaccine recipients had fewer local and systemic reactions than did DTP vaccinees. Reactions after the 18-month APDT vaccination were minimal in severity regardless of the vaccine previously received. Antibody responses to lymphocytosis-promoting factor and agglutinogens were more pronounced in DTP recipients; however, APDT recipients had a better serologic response to filamentous hemagglutinin, and responses to the 69K protein were equivalent. This APDT vaccine produces fewer reactions than the standard whole-cell DTP vaccine. The protective significance of the serologic responses to the APDT vaccine is unknown, but the greater response to filamentous hemagglutinin and equivalent response to the 69K protein c o m p a r e d with those to DTP vaccine seem promising. (J PEDIATR1991;119:194204) Presented in part at the Fifth International Symposium on Pertussis, Copenhagen, Denmark, Sept. 22, 1988; the joint meeting of the American Pediatric Society and the Society for Pediatric Research, Washington, D.C., April 29, 1989; and the International Symposium on Pertussis: Evaluation and Research on Acellular Pertussis Vaccines, in Shizuoka, Japan, Sept. 14, 1990. (In relation to these meetings, published in part: Tokai J Exp Clin Med 1988;13:21-28 and Pediatr Res 1989;25:175A.) Submitted for publication Nov. 19, 1990; accepted Feb. 8, 1991. Reprint requests: James D. Cherry, MD, Department of Pediatrics,
194
University of California at Los Angeles School of Medicine, Los Angeles, CA 90024-1752. *Dr. Mink is now at the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Washington, D.C.; Dr. Daum is at the University of Chicago School of Medicine, Chicago, Ill.; and Dr. Dekker is at Chiron Corp., Emeryville, Calif. **See Addendum for list of other members of the APDT Vaccine Study Group. 9/20/28583
Volumell9 Number2
APDT DTP ELISA EU FHA LPF
Compar~onofAPDT and DTP vaccines
Acellular pertussis-component DTP vaccine Diphtheria and tetanus toxoids and whole-cell pertussis-component vaccine, adsorbed Enzyme-linked immunosorbent assay ELISA unit Filamentous hemagglutinin Lymphocytosis-promoting factor
Currently licensed pertussis vaccines are associated with many reactions, 1,2 and development of a less reactogenic vaccine is desirable. In Japan, several acellular pertussiscomponent vaccines have been developed and used for routine immunization, a, 4 These vaccines produce minimal side effects, and their use is controlling epidemic pertussis in Japan. One Japanese acellular-component vaccine, manufactured by Takeda Chemical Industries, Osaka, Japan, was formulated into an APDT vaccine with diphtheria and tetanus toxoids prepared by Wyeth Laboratories, Philadelphia, Pa., and testing in the United States revealed few side effects. 510 More recently the Takeda acellular pertussis Component has been combined with Lederie Laboratories (Pearl River, N.Y.) diphtheria and tetanus toxoids. Members of our group previously compared Lederle/Takeda APDT vaccine with Lederle DTP vaccine administered as the fifth DTP immunization to 4- to 6-year-old children 11 and as the fourth DTP immunization administered to 17- to 24-month-old ehildrenl2; this APDT vaccine was immunogenic and less reactogenic than the whole-cell pertussiscomponent DTP vaccine. In this article the results of a multicenter randomized longitudinal double-blind study are reported in which Lederle/Takeda APDT vaccine was compared with Lederle DTP vaccine administered to 2-, 4-, and 6-month-old infants, with all subjects receiving APDT vaccine at 18 months of age. METHODS Subjects. Four-hundred ninety-seven healthy 2-monthold infants were enrolled at 10 study sites. In a double-blind manner, 252 children were randomly selected to receive DTP vaccine at 2, 4, and 6 months of age, and 245 children were randomly selected to receive APDT vaccine at the same ages. All children were scheduled to receive APDT vaccine at 18 months of age. Vaccine was administered in a volume of 0.5 ml into the anterior lateral thigh muscle through a 1-inch 25-gauge needle. The parents were requested to maintain a diary of local and systemic reactions for 10 days after immunization. Rectal temperature was recorded before immunization and 30 minutes and 3, 6, 24, 48, and 72 hours after immunization. The presence or absence of the following reactions was recorded at 30 minutes and at 3 and 6 hours after vaccination and daily thereafter for 10 days: local tenderness, vesicles, erythema, induration, swelling, and elevated site temperature; drowsiness, irrita-
195
bility, vomiting, and persistent or unusual crying. Antipyretic medication wa s not routinely administered but was recommended for rectal temperature -->39~ C. Reactogenicity and antipyretic administration data were obtained by telephone contact 1, 2, 3, and 14 days after each immunization. Medical office visits for infections and all hospitalizations were recorded between the 7-month follow-up visit and the 18-month APDT immunization. This study was approved by the institutional review boards at each institution. Informed consent was obtained from the parents or guardians after the design and purpose of the study were explained. Subject enrollment began May 1987, and the last subject completed the 19-month follow-up visit July 1989. Laboratory techniques. Serum samples were obtained by venipuncture for antibody measurements at 2 months (before the first immunization), 6 months (before the third immunization), 7 months, 18 months (before the fourth immunization), and 19 months of age. Because of insufficient serum volume, not all antibody values were determined for all children. Specific immunologic responses were assayed at Lederle Biologicals. An enzyme-linked immunosorbent assay was used to determine lymphocytosis-promoting factor and filamentous hemagglutinin antibody values, 13 and 69K protein antibodies were determined by ELISA as previously described) 2 At 2, 6, and 7 months of age, 69K protein antibody values were determined for subjects at only 2 of the 10 study sites. A microagglutination assay measured pertussis agglutinating antibodies using equal quantities of Bordetella pertussis strains 130 and 138 as the antigens. 13 Neutralizing antibodies to LPF were determined by the Chinese hamster ovary cell assay) 4 Antitoxin values for diphtheria were determined by the micro cell culture method using Vero cells, 15 and tetanus antitoxin values were determined by neutralization in mice. 16 Antibody values were excluded from analysis for subjects who were vaccinated outside of acceptable age intervals or who had blood drawn outside of acceptable postimmunization intervals. Acceptable age intervals for vaccination were defined as (number of subjects excluded in parentheses): dose 1, from 6 weeks to 3 months of age (5 subjects); dose 2, from 3.5 to 6 months and >6 weeks since first dose (32); dose 3, from 5 to 8 months and >6 weeks since second dose (48); and dose 4, from 15 to 21 months (6). The acceptable postimmunization interval was 3 to 9 weeks after the third dose for the 7-month blood draw (20 subjects), and after the fourth dose for the 19-month blood draw (27). Vaccines. The DTP vaccine was a single lot of commercially available licensed Lederle adsorbed vaccine (Tri-Immunol) containing 12.5 Lf of diphtheria toxoid and 5 Lf units of tetanus toxoid per dose, and the pertussis compo-
196
Table
Blurnberg et al.
The Journal of Pediatrics August 1991
I. F r e q u e n c y o f local and s y s t e m i c reactions within t h e first 72 hours after i m m u n i z a t i o n Dose I at 2 m o DTP (n = 252)
Dose 2 at 4 m o
APDT (n = 245)
DTP (n = 241)
APDT (n = 230)
Dose 3 al 6 m o DTP (n = 231)
Dose 4 at 18 m o
APDT (n = 223)
APDT (n = 397")
Local reactions Tenderness Erythema Any >20 mm Induration Any >20 mm Swelling >10 mm Site Temperature Warm or hot Hot Vesicles
48.1
8.6~"
27.8
4.8?
25.1
5.4?
18.3
44.1 8.3
22.9"~ 0t
44.4 7.9
28.3t 3.0:~
43.3 3,5
25,1 + 2,7
26.6 11.3
42.1 10,3 21,8
7.81" 1.2t 4.9~"
37.3 8.3 14.9
15.2t 0.9t 8,2~
37,7 4.3 15.1
16,6? 1.8 7.2~:
23,6 7.5 14.2
35.3 1.6 0.4
9.0~ 0.4 0
24,1 3.7 0.8
8,7t OCT 0
23.8 1.3 0.9
4.9~" 0 0
13,3 2.3 0,3
37.7 1.6
4.5t 1.2
34,0 3.3
9.1t 0~
39.7 6,5
14.8t" 1.4~+
21.2 2.8
38.9 7.5
19.2r 0.8t
38.6 1.2
l 7.8r 0.9
41.1 3.5
23.2"~ 0.9
15, l 0.8
31.0 7.1 5.2 5.6 4,0 0
17,61" 1.6~ 3.7 1.2:t: 0~ 0
l 9,9 1.7 4.6 3.3 0.8 0
12.6,~ 1.3 3.0 1,3 0 0
22.3 1,8 4.8 0.9 0 0.4
10,01" 0.9 0.9~ 0.9 1.4 0.4
2.8 0.3 1.5 0.3 0.3 0
Systemic reactions Rectal Temperature _>38.0 ~ C >_39.0 ~ C Irritability Any Markedw Drowsiness Any Marked Vomiting Persistent crying Unusual crying Hypotonic-hyporesponsive episode Seizures
0
0
0
0
0
0
0
Values are percentage of children vaccinated experiencing designated event. "199 subjects from the initial DTP group and I98 subjects from the initial APDT group. Sp ~0.001 DTP versus APDT. Sp 40.5 ~ C Other TOTAL
DTP group
APDT group
19 10 7 4
19 1l 7 3
1
2
7 1 1 3* 53
1 1 0 35 47
*One subject each with failure to thrive, development of immunodeficiency disorder, and death. tOne subject with difficulty obtaining blood samples and two subjects with frequent illnesses.
Volume 119 Number 2
Ld (/3
Comparison o f A P D T and DTP vaccines
250
LPF(=16 T LPF(=16 /
Q----oAPDT: P r e - l m m *--* DTP: P r e - l m m
o - - - - o A P D T : P r e - l r n m LPF)16 =--= DTP: P r e - l m m LPF>16
+1
#
I--
o----oAPDT: P r e - l m m o--. DTP: P r e - l m m
CH0(=32 CH0(=32
o-----oAPDT: P r e - l m m =--= DTP: P r e - l m m
CH0)32 CH0)32
1200-
g 150
LO r
1600
+1
200
c ,< U3
Ld 03
19 7
.s +~
800-
~O
400-
100 -
L) "C_
5(3-
E
o (D C9
~ 2
6
7 Months
APDT N: DTP N:
Pre-lmm
LPF (=16 Pre-lmm LPF )16
APDT N: DTP N:
107 111 126 128
84 83 102 100
18
19
72 71 83 82
68 66 77 73
83 79 96 96
2
6
7 Months
Pre-lmm CHO (=32
APDT N: DTP N:
Pre-lmm
APDTN:
DTP N:
CHO )32
112 124 96 92
80 60 66 64
18
19
57 65 47 44
56 61 42 43
of age
77 88 61 58
B
A Ld 6O §
0
of age
125 o----oAPDT: P r e - l m m e--e DTP: P r e - l m m
FHA(=8 FHA(=8
n -oAPDT: P r e - l m m FHA>8 ,--m DTP: Pre Irnm FHA>8
o----oAPDT: P r e - t m m A g g l ( = 8 9 --* DTP: P r e - l r n m A g g l ( = 8
+1
o-----oAPDT: P r e - l m m A g g l ) 8 =--. DTP: P r e - l m m A g g l ) 8
150
100 -
C < (/3 LO
g 9
,\ ..\
,//"
25-
/"t
/ /'//~
\, ',\
c 100
o "u_
/ /" i~ /'i/--/t
\"\
.//-
/
//'
/" ~k I/I.-i/~'\
50
"oc
N E
/
//{k,
75-
E o co
50
/ /
2
o_
o 9 (.D
Qs 2
6
7 Months
Pre-lmm FHA
