Effect of Concurrent Viral Infection on Systemic and Local Antibody Responses to Live Attenuated and Enhanced-Potency Inactivated Poliovirus Vaccines Howard Faden, MD, Linda
Objective.\p=m-\Todetermine the effect of an asymptomatic nonpolioviral infection on the immune response to poliovi\s=b\
rus
vaccines.
Design.\p=m-\Opencomparative trial. Setting.\p=m-\Well-childclinic at The Children's Hospital of
Buffalo,
NY.
Participants.\p=m-\Twenty-sevenhealthy infants infected with nonpolioviruses and 27 healthy controls matched for
age and vaccine group. Interventions.\p=m-\Trivalentoral attenuated poliovirus vaccine or enhanced potency inactivated vaccine administered at ages 4 and 12 months. Measurements/Main Results.\p=m-\Neutralizingantibody to poliovirus serotypes 1, 2, and 3 were determined in the serum and nasopharyngeal secretion samples obtained at ages 4, 5,12, and 13 months. The IgA antibody titers for polioviruses 1,2, and 3 were measured in nasopharyngeal secretion samples during the same periods. Antibody responses to poliovirus vaccines were similar in coinfected subjects and healthy controls at ages 5 and 13 months, except for serum neutralizing antibody that was significantly elevated in the controls compared with coinfected subjects (geometric mean [\m=+-\SD]antibody titers, 12.7\m=+-\1.6vs 11.5\m=+-\1.7).Concurrent viral infections affected the immune response in recipients of the oral poliovirus vaccine and the enhanced\x=req-\ potency inactivated poliovirus vaccine similarly. The immune response to polioviruses 1 and 3 were more adversely affected by coinfection than was the immune response to poliovirus 2. Conclusion.\p=m-\Concurrentasymptomatic viral infections minimally impaired the immune response to poliovirus vaccines. The adverse effects of coinfection were considered clinically insignificant.
(AJDC. 1992;146:1320-1323)
Accepted for publication June 16,
PhD
(OPVs). Advantages and disadvantages of each vaccine have been reviewed previously.1"5 One of the criticisms against OPV has been its lesser efficacy in developing countries.6 The reasons for the poor outcome with OPV are not entirely understood. Differences in the uptake of OPV may be due to interference by concurrent viral infections, malnutrition, and the presence of inhibitory substances in the intestines.7,8 The present report was designed to determine the effect of an asymptomatic nonpolioviral infection on the immune response to poliovirus vaccines. PATIENTS, MATERIALS,
AND METHODS
Study Group
Boys and girls from the Buffalo (NY) community were enrolled between the ages of 6 and 10 weeks. The infants were free of ill¬ ness at the time of immunization.
Study Design The infants, all immunized with the OPV and /or the enhancedpotency inactivated poliovirus vaccine (EIPV), were assigned to one of the following four groups: OPV-OPV-OPV (group A), EIPV-EIPV-EIPV (group B), EIPV-OPV-OPV (group C), or EIPVEIPV-OPV (group D).9 The vaccines were administered at ages 2, 4, and 12 months. Serum samples were collected at the time of immunization and 1 month later for the determination of neu¬ tralizing antibody titers against poliovirus types 1, 2, and 3. Na¬ sopharyngeal specimens were collected during the same period for the determination of neutralizing and IgA-specific antibody titers. Nasopharyngeal and fecal samples were collected at ages 4,5,12, and 13 months and cultured. Patients were excluded from analysis if they had fewer than three visits, were older than 13.5 weeks at their first visit, were given the wrong vaccine, or had an unacceptable time span between visits. A patient excluded at one visit was excluded at all subsequent visits.
Vaccines the past 40 of effective poliovirus vaccines
poliomyelitis during Theyearsdramatic decline result widespread and live oral
in of the is the inactivated parenteral
Duffy,
use
1992. From the Department of Pediatrics (Drs Faden and Duffy), Division of Infectious Diseases (Drs Faden and Duffy), State University of New York at Buffalo, and The Children's Hospital of Buffalo (Drs Faden and Duffy), Women and Children's Health Research Foundation (Dr Duffy). Reprint requests to Division of Infectious Diseases, The Children's Hospital of Buffalo, 219 Bryant St, Buffalo, NY 14222 (Dr Faden).
Oral vaccine (Orimune; Lederle, Wayne, NJ) prepared in mon¬ key kidney cells contained antigen doses of poliovirus type 1,1055 to 1064 times the median tissue culture infective dose; type 2,1045 to 1055 times the median tissue culture infective dose; and type 3, 1052 to 1062 times the median tissue culture infective dose. The vaccine was stored at -70°C until use and administered orally in 0.5-mL volumes. Inactivated vaccine (Imovax Polio; Merieux Institute, Lyon, France) prepared in Vero cells contained antigen doses of polio¬ virus type 1, 40 D antigen units (DAU); type 2, 8 DAU; and type 3, 32 DAU. It was stored at 4°C and administered by subcutane¬ ous injection of 0.5-mL volumes.
Downloaded From: http://archpedi.jamanetwork.com/ by a Western University User on 06/09/2015
Table 1.—Number of Patient Visits Immunization Group*
Table 3.—Geometrie (Log Base 2) Mean Titers of Antibody to Polioviruses 1, 2, and 3
by
Age at Visit,
Nonpolioviruses)
Group
No. of Patients
A
23
22 (3)
22 (2)
65
57
(7) 17(4)
53 (5)
Immunization
C
17
D
18
|4 12
17(2) 16(4) 123 Total 108(13) 'Patients were assigned to one of four immunization groups: A, OPVOPV-OPV; B, EIPV-EIPV-EIPV; C, EIPV-OPV-OPV; or D, EIPV-EIPVOPV, where OPV indicates oral polio vaccine; and EIPV, enhancedpotency inactivated poliovirus vaccine. 17(0) 113(14)
2.—Nonpolioviruses Isolated From Nasopharyngeal and Stool Specimens*
Table Immunization
Age at Visit, 4
A
B
CA 16, CB 5, PF 3t CA 16, CB 4, CB 4, EC 22, AD,* RO, RO
CB 4, PF 3t CA 9, CB 2, EC 3, 6, AD+
C
AD, AD, EC 3, 18
CB 5, EC 22t
12
CB 4, AD, AD, EC 6 *Patients were assigned to one of four immunization groups: A, OPVOPV-OPV; B, EIPV-EIPV-EIPV; C, EIPV-OPV-OPV; or D, EIPV-EIPVOPV where OPV indicates oral polio vaccines; and EIPV, enhancedpotency inactivated poliovirus vaccine. CA indicates coxsackie A virus; CB, coxsackie virus; PF, parainfluenza virus; EC, echovirus; AD, ad¬ enovirus; and RO, rotavirus. Numbers beside virus abbreviations denote D
...
tNonpolioviruses
isolated from
Age at Antibody Response, mo
nasopharyngeal samples. nasopharyngeal secretion samples.
^Same infant had AD in stool and
Collection of Specimens Venous blood (1 to 3 mL) samples were collected for antibody determination. The serum samples were separated and stored at -20°C until testing. Nasopharyngeal secretions (NPS) were col¬ lected with a soft rubber catheter placed into both nasal passages. Secretions were mixed with 2 mL of phosphate-buffered saline (PBS) for antibody determination. Suspension (0.2 mL) was added to virus transport medium, minimal essential medium (MEM) with 5% fetal calf serum, for virus isolation. Fecal specimens were collected from soiled diapers. A 10% homogenate of stool in PBS was prepared and centrifuged, and the supernatant was used for culture.
Neutralizing Antibody Determinations Briefly, 50 µ of the sample was diluted in Eagle's MEM with 2% fetal calf serum in 96-well flat-bottom microtissue culture plates (Nunc, Naperville, 111). Poliovirus type 1 (Mahoney; ATCC, Rockville, Md), type 2 (Lansing; ATCC), or type 3 (Leon; ATCC), containing 25 to 50 median tissue culture infective doses per 50 µ , was added, and the preparation was incubated overnight at 36°C with 5% carbon dioxide. Vero cells (100 µ containing 10 000 cells) were added; the solution was mixed and incubated at 36°C with 5% carbon dioxide for 7 days. The highest dilution of specimen that showed no cytopathic effect was the titer of neutralizing antibody. A tissue culture control, a virus control, and a serum control positive for antibody were included in each assay. The lowest and highest dilutions, respectively, of sample tested were 1:10 for serum and 1:4 for NPS, and 1:81920 for each.
1
-
Coinfected
Controls
4.4±2.9 8.4+2.5 7.5±2.0 11.5±1.7
4.2±2.7 9.0±2.7 7.9±1.7 12.7±1.6*
4 5 12
1.2±0.5 2.0±1.3
2.1 ±1.6
13
3.0±2.3
neutralizing antibody
Serum
4 5 12 13
Nasopharyngeal neutralizing antibody
1.6+1.2
Nasopharyngeal IgA antibody 4 5 12 13
mo
-
Group
serotype.
Mean±SD
mo
(No. With
2.5±1.5 3.2±1.9 5.5±1.8 5.4±1.8
*Mann-Whitney
rank
sum
P
Objective.\p=m-\Todetermine the effect of an asymptomatic nonpolioviral infection on the immune response to poliovi\s=b\
rus
vaccines.
Design.\p=m-\Opencomparative trial. Setting.\p=m-\Well-childclinic at The Children's Hospital of
Buffalo,
NY.
Participants.\p=m-\Twenty-sevenhealthy infants infected with nonpolioviruses and 27 healthy controls matched for
age and vaccine group. Interventions.\p=m-\Trivalentoral attenuated poliovirus vaccine or enhanced potency inactivated vaccine administered at ages 4 and 12 months. Measurements/Main Results.\p=m-\Neutralizingantibody to poliovirus serotypes 1, 2, and 3 were determined in the serum and nasopharyngeal secretion samples obtained at ages 4, 5,12, and 13 months. The IgA antibody titers for polioviruses 1,2, and 3 were measured in nasopharyngeal secretion samples during the same periods. Antibody responses to poliovirus vaccines were similar in coinfected subjects and healthy controls at ages 5 and 13 months, except for serum neutralizing antibody that was significantly elevated in the controls compared with coinfected subjects (geometric mean [\m=+-\SD]antibody titers, 12.7\m=+-\1.6vs 11.5\m=+-\1.7).Concurrent viral infections affected the immune response in recipients of the oral poliovirus vaccine and the enhanced\x=req-\ potency inactivated poliovirus vaccine similarly. The immune response to polioviruses 1 and 3 were more adversely affected by coinfection than was the immune response to poliovirus 2. Conclusion.\p=m-\Concurrentasymptomatic viral infections minimally impaired the immune response to poliovirus vaccines. The adverse effects of coinfection were considered clinically insignificant.
(AJDC. 1992;146:1320-1323)
Accepted for publication June 16,
PhD
(OPVs). Advantages and disadvantages of each vaccine have been reviewed previously.1"5 One of the criticisms against OPV has been its lesser efficacy in developing countries.6 The reasons for the poor outcome with OPV are not entirely understood. Differences in the uptake of OPV may be due to interference by concurrent viral infections, malnutrition, and the presence of inhibitory substances in the intestines.7,8 The present report was designed to determine the effect of an asymptomatic nonpolioviral infection on the immune response to poliovirus vaccines. PATIENTS, MATERIALS,
AND METHODS
Study Group
Boys and girls from the Buffalo (NY) community were enrolled between the ages of 6 and 10 weeks. The infants were free of ill¬ ness at the time of immunization.
Study Design The infants, all immunized with the OPV and /or the enhancedpotency inactivated poliovirus vaccine (EIPV), were assigned to one of the following four groups: OPV-OPV-OPV (group A), EIPV-EIPV-EIPV (group B), EIPV-OPV-OPV (group C), or EIPVEIPV-OPV (group D).9 The vaccines were administered at ages 2, 4, and 12 months. Serum samples were collected at the time of immunization and 1 month later for the determination of neu¬ tralizing antibody titers against poliovirus types 1, 2, and 3. Na¬ sopharyngeal specimens were collected during the same period for the determination of neutralizing and IgA-specific antibody titers. Nasopharyngeal and fecal samples were collected at ages 4,5,12, and 13 months and cultured. Patients were excluded from analysis if they had fewer than three visits, were older than 13.5 weeks at their first visit, were given the wrong vaccine, or had an unacceptable time span between visits. A patient excluded at one visit was excluded at all subsequent visits.
Vaccines the past 40 of effective poliovirus vaccines
poliomyelitis during Theyearsdramatic decline result widespread and live oral
in of the is the inactivated parenteral
Duffy,
use
1992. From the Department of Pediatrics (Drs Faden and Duffy), Division of Infectious Diseases (Drs Faden and Duffy), State University of New York at Buffalo, and The Children's Hospital of Buffalo (Drs Faden and Duffy), Women and Children's Health Research Foundation (Dr Duffy). Reprint requests to Division of Infectious Diseases, The Children's Hospital of Buffalo, 219 Bryant St, Buffalo, NY 14222 (Dr Faden).
Oral vaccine (Orimune; Lederle, Wayne, NJ) prepared in mon¬ key kidney cells contained antigen doses of poliovirus type 1,1055 to 1064 times the median tissue culture infective dose; type 2,1045 to 1055 times the median tissue culture infective dose; and type 3, 1052 to 1062 times the median tissue culture infective dose. The vaccine was stored at -70°C until use and administered orally in 0.5-mL volumes. Inactivated vaccine (Imovax Polio; Merieux Institute, Lyon, France) prepared in Vero cells contained antigen doses of polio¬ virus type 1, 40 D antigen units (DAU); type 2, 8 DAU; and type 3, 32 DAU. It was stored at 4°C and administered by subcutane¬ ous injection of 0.5-mL volumes.
Downloaded From: http://archpedi.jamanetwork.com/ by a Western University User on 06/09/2015
Table 1.—Number of Patient Visits Immunization Group*
Table 3.—Geometrie (Log Base 2) Mean Titers of Antibody to Polioviruses 1, 2, and 3
by
Age at Visit,
Nonpolioviruses)
Group
No. of Patients
A
23
22 (3)
22 (2)
65
57
(7) 17(4)
53 (5)
Immunization
C
17
D
18
|4 12
17(2) 16(4) 123 Total 108(13) 'Patients were assigned to one of four immunization groups: A, OPVOPV-OPV; B, EIPV-EIPV-EIPV; C, EIPV-OPV-OPV; or D, EIPV-EIPVOPV, where OPV indicates oral polio vaccine; and EIPV, enhancedpotency inactivated poliovirus vaccine. 17(0) 113(14)
2.—Nonpolioviruses Isolated From Nasopharyngeal and Stool Specimens*
Table Immunization
Age at Visit, 4
A
B
CA 16, CB 5, PF 3t CA 16, CB 4, CB 4, EC 22, AD,* RO, RO
CB 4, PF 3t CA 9, CB 2, EC 3, 6, AD+
C
AD, AD, EC 3, 18
CB 5, EC 22t
12
CB 4, AD, AD, EC 6 *Patients were assigned to one of four immunization groups: A, OPVOPV-OPV; B, EIPV-EIPV-EIPV; C, EIPV-OPV-OPV; or D, EIPV-EIPVOPV where OPV indicates oral polio vaccines; and EIPV, enhancedpotency inactivated poliovirus vaccine. CA indicates coxsackie A virus; CB, coxsackie virus; PF, parainfluenza virus; EC, echovirus; AD, ad¬ enovirus; and RO, rotavirus. Numbers beside virus abbreviations denote D
...
tNonpolioviruses
isolated from
Age at Antibody Response, mo
nasopharyngeal samples. nasopharyngeal secretion samples.
^Same infant had AD in stool and
Collection of Specimens Venous blood (1 to 3 mL) samples were collected for antibody determination. The serum samples were separated and stored at -20°C until testing. Nasopharyngeal secretions (NPS) were col¬ lected with a soft rubber catheter placed into both nasal passages. Secretions were mixed with 2 mL of phosphate-buffered saline (PBS) for antibody determination. Suspension (0.2 mL) was added to virus transport medium, minimal essential medium (MEM) with 5% fetal calf serum, for virus isolation. Fecal specimens were collected from soiled diapers. A 10% homogenate of stool in PBS was prepared and centrifuged, and the supernatant was used for culture.
Neutralizing Antibody Determinations Briefly, 50 µ of the sample was diluted in Eagle's MEM with 2% fetal calf serum in 96-well flat-bottom microtissue culture plates (Nunc, Naperville, 111). Poliovirus type 1 (Mahoney; ATCC, Rockville, Md), type 2 (Lansing; ATCC), or type 3 (Leon; ATCC), containing 25 to 50 median tissue culture infective doses per 50 µ , was added, and the preparation was incubated overnight at 36°C with 5% carbon dioxide. Vero cells (100 µ containing 10 000 cells) were added; the solution was mixed and incubated at 36°C with 5% carbon dioxide for 7 days. The highest dilution of specimen that showed no cytopathic effect was the titer of neutralizing antibody. A tissue culture control, a virus control, and a serum control positive for antibody were included in each assay. The lowest and highest dilutions, respectively, of sample tested were 1:10 for serum and 1:4 for NPS, and 1:81920 for each.
1
-
Coinfected
Controls
4.4±2.9 8.4+2.5 7.5±2.0 11.5±1.7
4.2±2.7 9.0±2.7 7.9±1.7 12.7±1.6*
4 5 12
1.2±0.5 2.0±1.3
2.1 ±1.6
13
3.0±2.3
neutralizing antibody
Serum
4 5 12 13
Nasopharyngeal neutralizing antibody
1.6+1.2
Nasopharyngeal IgA antibody 4 5 12 13
mo
-
Group
serotype.
Mean±SD
mo
(No. With
2.5±1.5 3.2±1.9 5.5±1.8 5.4±1.8
*Mann-Whitney
rank
sum
P
