EUROPEAN JOURNAL
Eur. J. Epidemiol. 0392-2990 March 1992, p. 211-216
Vol. 8, No. 2
OF EPIDEMIOLOGY
ANTIBODY RESPONSE TO INACTIVATED POLIO VACCINE (E-IPV) IN CHILDREN BORN TO HIV POSITIVE MOTHERS M. BARB1.1, M. BARDARE**, C. LURASCHI*, G. ZEHENDER*, M. CLERICI SCHOELLER**, and G. FERRARIS** *Institute o f Virology - Universi~ o f Milan - Via C. P a s c a l 38 - 20133 Milano - Italy. **First Pediatric Clinic - University o f Milan.
Key words: HIV - Children - Immunization - Poliovaccine
In order to evaluate the response to immunization of HIV-infected children we studied the humoral response to an enhanced potency inactivated poliovaccine (E-IPV) of 43 children born of H1V seropositive mothers. All these subjects have been followed for 32 (15-48) months in order to ascertain their infection status. After a course of 2 doses of E-IPV, 88% of children had neutralizing antibody (n.a.) titers > 1:4 to the 3 poliovirus serotypes and 100% to at least 2 polio strains. No statistically significant differences both as rates of n.a. positive subjects and as antibody levels were found between H1V infected children and those who lost HIV antibodies. The poorest response was observed in subjects with full-blown immunodeficiency (CD4 < 1000/mm3, reduced response to PWM). Sixteen children also received a booster dose of vaccine one year after the completion of the primary cycle. Infected and non-infected subjects responded to the same extent with high levels of n.a. to this immunization. Interestingly, the recall dose was also able to induce high n.a. titers in those HIV infected children who showed significant decreases of n.a. titers in the months following the end of the primary cycle.
INTRODUCTION
The weight of pediatric HIV infection, once thought of as a problem restricted only to a few sectors of society, and linked to particular epidemiological situations, is now becoming prevalent throughout the world. The most c o m m o n mode of transmission for pediatric HIV infection if vertical, namely from mother to child. Therefore, the frequency o f this infection is growing, depending on the increase in the rate of w o m e n in their childbearing age who are HIV infected as a result either o f heterosexual transmission or of high risk behaviours (i.e. drug addiction) (16). 1 C o r r e s p o n d i n g author.
211
A serious problem arising from the diffusion of pediatric HIV infection concerns the application of vaccine prophylaxis to children born to seropositive mothers. Indeed, as opposed to the recognized need to give these children routine childhood vaccinations, some doubts have arisen on a theoretical ground both to the harmlessness of antigenic stimulation in subjects potentially infected with HIV and the efficacy of the vaccinations themselves in terms of the extent and duration of the antibody response (7, 15, 19, 21). The only negative data reported so far in the literature involved adults immunised with live tuberculosis and smallpox vaccines (4, 14, 18). Consequently, as far as childhood immunization is concerned, both international (WHO) and national health authorities (7, 20) feel that is better to follow
Barbi M. et aL
Eur. J. Epidemiol.
the normal schedule for all babies who are HIV seropositive at birth. However, Italian as well USA health authorities have decided, on a prudential basis, to suggest the use of the inactivated poliovaccine (Salk type, IPV) rather than the attenuated poliovaccine (Sabin type, OPV) which is used in the general population. In fact, available data on asymptomatic HIV-infected children do not suggest that they are at increased risk of adverse consequences from OPV. The indication of using IPV lies on the possibility that family members may be immunocompromised because of AIDS or HIV infection and may be at increased risk for paralysis from contact with an OPV virus (8). With regards to an evaluation of the immunological efficacy of vaccinating subjects already infected with HIV, in the case of children the situation is complicated by the well-known difficulty of defining the true state of HIV infection of seropositive babies at birth. Indeed, the possible persistence up to the 15th or 18th month of maternal HIV antibodies do not allow the establishment of whether the seropositive state in the first months of life is transitory or whether it is in response to an infection transmitted by the mother. Data in the literature on the consequences of vaccinating such patients are scarce, result from retrospective studies (11), or stem from an examination of clinical records only involving children with symptoms. The aim of the present study was to determine the immunogenicity of polio vaccination in a group of babies who were HIV positive at birth. The antibody response was evaluated in the light of the state of HIV infection of each subject, ascertained during the course of a thorough virological and clinical follow-up.
Polio vaccination An inactivated trivalent vaccine with an enhanced antigenic content (E-IPV) was used. This corresponds to 32, 8 and 40 DU of polioviruses 1, 2 and 3 respectively (IPV-M6rieux, Istituto M6rieux, Italy). Each subject was given 3 intramuscular doses of vaccine at monthly intervals (initial cycle). Sixteen babies received a booster dose about one year after the final dose of the initial cycle.
Samples In order to evaluate the response to vaccination, we examined at least two samples of serum from each baby. One of these, taken before the first injection of vaccine, constituted the basic sample while the second was taken one month after the second inoculation. Further serum specimens were collected from children who received the booster dose. These samples were drawn before and at least one month after the booster.
Serological tests The neutralizing polio antibodies (n.a.) were titrated in microplates on VERO cells. Each serum dilution (from 1:4 to 1:256) was incubated for one hour at room temperature with 100 DC50 of each of the three poliovirus serotypes (attenuated Sabin strains). After the addition of the cells and subsequent incubation for 5 days at 37°C, the results were read. The highest dilution of serum capable of inhibiting the appearance of the viral cytopathic effect was taken as the n.a. titer. The test for antibodies to HIV was carried out by ELISA (Abbot Labs) and Western Blot (Sorin Biomedica).
MATERIALS AND METHODS
Statistical analysis Subjects All children born to HIV seronegative mothers who attended the 1st Pediatric Department since 1988 were enrolled in this study, giving a total of 43 children. The mothers belonged to risk categories, 40 of the 43 women were or had been drug abusers and 3 were partners of HIV seropositive men. The subjects, 17 males and 26 females with a mean age of 8.1 months (range 4-42), were classified at the beginning of E-IPV immunization as follows: P0 26, PI 4 and P2 13. All the children were still seropositive for HIV antibodies at the beginning of the vaccination cycle. Follow-up The subjects studied had checkups every three months for their clinical and immunological condition, as well as a serological ascertainment of their state of HIV infection. 212
Differences between frequencies were compared by means of either the chi-square test with Yates correction or the Fisher's exact method. Geometric mean titer comparisons were performed employing the Student's "t" test. RESULTS
Clinical and immunological evolution At the beginning of the vaccination cycle all 43 children were seropositive for HIV antibodies in ELISA and WB; during the follow-up, which lasted 32 months (range 15-48 months), 26 out of 43 children progressively lost HIV antibodies (group A) at a mean age of 11.6 months (range 4.5-17 months). None of the children belonging to group A ever showed clinical or immunological signs related to HIV infection. They have all been tested for virus isolation
Poliovaccine in HIV+ve children
Vol. 8, 1992
with viral culture and polymerase chain reaction and they were all found negative. The remaining 17 children (group B) showed clinical or immunological signs related to HIV infection before the beginning of the vaccination cycle; in accordance with CDC (Center for Disease Control, Atlanta) criteria (5), 4 were classified as P1B (clinically asymptomatic with immunological alterations) while the other 13 were classified as P2 (clinically symptomatic), even though none of them had AIDS. The immunological features of the 17 HIV-infected children, at the beginning of the vaccination cycle, are represented in Table 1. During the follow-up (the follow-up period was the entire vaccination cycle and included the booster when executed) the clinical status of the 17 children evolved as follow: 5 out of 13 children previously classified as P2 developed full-blown AIDS, and 2 died of pulmonary opportunistic infections. Of the 4 previously classified as P1, 3 became P2 due to the appearance of minor clinical signs related to HIV infection (hepatosplenomegaly and lymphoadenopathy). The immunological situation of the infected children at the end of the vaccination cycle is reported in Table 2. An important involvement of the immunological system marked by frequent polytopic infections was present in 5 children who started treatment with
intravenous immunoglobulins (Endobulin 400 mg/kg) before the beginning of the vaccination cycle.
Response to the polio vaccination The study of humoral response to polio vaccination was performed on all 43 children; 27 of these were studied following the vaccination cycle, 12 were studied after the vaccination cycle and after the booster dose, and 4 were studied exclusively after the booster dose (Figure 1). The response of the HIV seronegative children (group A) was compared with that of HIV-infected subjects (group B). We excluded from this evaluation those HIV-infected babies who had received infusions of gammaglobulin during their initial vaccination cycle and 5 babies (1 infected and 4 seronegative) who, as we subsequently discovered, had already received a dose of OPV. At the end of the first E-IPV cycle all the babies were found to be protected (n.a. titer > 1:4) against at least 2 strains of poliovirus, and 88% of the subjects under study had produced antibodies against all the serotypes. The response frequencies in the two groups of children didn't differ from one another. The extent of the immune response has been ascertained by taking the geometric mean titers (GMT) of n.a. obtained (Table 3).
TABLE 1. - Immunological findings of 17 HIV-infected children before vaccination with E-IPV. Hypergamma globulinemia P1 ( n = 4 )
4/4 (100 %)
CD4/CD8 < 1
CD4 < 2000 /mm 3
0/4 ( 0 % )
0/4
(0%)
Response to PWM reduced 0/4 ( 0 % )
P2 (n = 13)
11/13 (84.6%)
4/13 (30.7%)
5/13" (38.5%)
3/13 (23.0%)
Total
15/17 (88.2%)
4/17 (23.5%)
5/17 (29.4%)
3/17 (17.6%)
* None showed CD4+ lymphocytes < 1000/mm3
TABLE 2. - Immunological evaluation of 17 HIV-infected children at the end of the E-IPV vaccination cycle. Hypergamma globulinemia P1 ( n = 1) P2 (n --- 11)* AIDS ( n = 5)* Total
1/1 (100%)
CD4/CD8 < 1
0/1 (
O)
C D 4 / < 2000 /mm 0/1 (
O)
Response to PWM reduced 0/1 (
O)
11/11 (100%)
9/11 (81.8%)
3/11 (27.2%)
1/11 ( 90 %)
5/5 (100%)
5/5 (100 %)
5/5 (100 %)
5/5 (100 %)
17/17 (100%)
14/17 (82.3%)
8/17 (47.0%)
6/17 (35.2%)
* The mean value of CD4+ lymphocytes globally considered was: in P2 children = l198/mm3 in AIDS children = 530/ram3 213
Barbi M. et al.
TABLE 3.
-
Eur. J. Epidemiol.
Humoral response to the primary cycle of E-IPV immunization and HIV infection status. Response to
Subjects
N
polio 1
polio 2
polio 3
%*
GMT
%*
GMT
%*
GMT
20
100
1 • 27
100
1 • 46
85
1 • 26**
9
100
1 • 29
100
1 • 54
88
1 " 8 **
^
Group A ^
Group B See text
* Rate of children with n.a. titers > 1 : 4 ** P < 0.05
Response to the booster
/I 'm°.l 'm" I J 1
1~1".
A general and marked increase in the titers was observed after administration of the booster dose. For members of both groups, the GMTs then obtained were found to be considerably higher than those obtained after the initial cycle, with the single exception of the response to poliovims 2 in subjects suffering from HIV infection. On the other hand, no significant difference was found between the GMTs obtained from HIV-seronegative children and those who were infected (Table 4).
? ,m°.l/
2
• -
...
3
4
IPV "." s e r u m s = m p l e
Samples t ~
t ~
1+ 2
: 27
subjects
1+2~3+4
: 12
,,
3+4
: 4
',
TABLE 4. - Response to a booster dose of E-IPV and HIV infection status. G M T of neutralizing polio antibodies Subjects
Figure 1. - Time-line of the events over time for the study group.
N
polio 1
polio 2
polio 3
10
1 : 138
1 : 194
1 : 239
6
1 : 81
1 : 64
1 : 144
^
Group A ^
Group B
No significant differences were found in the responses to polio 1 and 2, but the HIV-infected infants responded less well than the uninfected subjects to the type 3 polio virus (p < 0.05). With regards to the 5 cases already vaccinated with OPV, whose basic serum samples already presented andibodies to one or two strains of poliovirus, their response to the other serotypes was found to be comparable to that of the other children.
See text.
Side-effects No side-effects of any sort have been observed. In particular, there were no cases in which the vaccination coincided with clinical and/or immunological deterioration of the subject treated.
Persistence of ~mti-polio antibodies DISCUSSION
With regards to the persistence of antibodies produced after the initial doses of E-IPV, this could be ascertained in only 7 cases. During an interval of 6 months to 1 year from the last vaccination, antibody titers decreased significantly (> 4 times) in the 3 infected babies, but remained unchanged in the 4 subjects belonging to group A. 214
Studies to evaluate the immune response capacity of HIV-infected subjects have indicated that infection by this virus reduces their ability to develop a response against a variety of antigens such as tetanus and diphteria toxoids (2, 3, 19), pneumococcal and influenza vaccines (6, 13, 17), and hepatitis vaccine (10).
Vol. 8, 1992
Poliovaccine in HIV+ve children
With regards to the polio vaccine, however, retrospective studies performed on infected children have shown that both the inactivated and attenuated vaccines are, to some extent, effective. Children vaccinated between 1 month and 15 years earlier had a protective level of antibodies towardsthe poliovirus type 2, in 21 of the 23 cases vaccinated with OPV and in 3 out of 3 cases vaccinated with IPV. The antibody titers were found to be in correlation with the stage of HIV infection (9). In another study the response to three doses of IPV was found to be lower in infected subjects with impaired immunity than that in infected subjects with normal lymphoproliferative responses (1). The present survey has taken into consideration seropositive children whose HIV infection status was unknown because the majority of them were younger than 15 months at the beginning of the study. The good response to vaccination found in HIVinfected children is not surprising if we consider that the immunological system of these babies was not involved when the cycle of polio vaccine was started. The inversion of CD4/CD8 ratio was present in only 23.5% of the children and no one presented a CD4+ lymphocyte number < 1000/ram 3. In fact in the 5 babies with CD4+ < 1000/mm 3and impaired response to PWM, who were treated with IVIG for polytopic infections, the response to vaccine was poor. The significant reduction of n.a. titers detected o n l y in infected subjects needs to be emphasized; nevertheless the good response of the majority of these children to a booster dose suggests that a recall dose in all these children is recommended. How long immunity lasts after the booster dose remains to be seen. Aknowledgements
This study was supported by Regione Lombardia, Convenzione "Indagini diagnostiche ed epidemiologichenel campo delle infezioni da virus HTLV III/LAV'. REFERENCES 1. Bernstein L.J., Ochs H.D., Wedgwood R.J. et aL (1985): Defective humoral immunity in pediatric acquired immune deficiency syndrome. J. Pediatr. 107: 352357. 2. Blanche S., Le Diest F., Fisher A., et al. (1986): Longitudinal study of 18 children with perinatal LAV/HTLV III infection: attempt at prognostic evaluation. J. Pediatr. 109: 965-970.
5.
CDC (1987): Classification system for immunodeficiency virus (HIV) infection in children under 13 years of age. MMWR 36: 225-235.
6. Fikrig S.M., Menez- Bautista R., Menikoff tt., et al. (1987): Response of HW infected children to pneumococcal vaccine. Pediatr. Res. 21:311 A. 7. Immunization Practices Advisory Committee (1986): Immunization of children infected with human Tlymphotropic virus type III/lymphadenopathyassociated virus. MMWR 35: 595-598, 603-606. 8. Immunization Practices Advisory Committee (1989): General recommendations on immunization. MMWR 38: 205-227. 9. Krasinki K., Borkowsky W. (1987): Response to polio vaccination in children infected with human immunodeficiency virus. Pediatr. Res. 21:328 A.
10. Mannucci P.M., Zanetti A.R., Gringeri A., et al. (1989): Long-term immunogenicity of a plasma derived hepatitis B vaccine in anti-HW positive and anti-HIV negative hemophilics. Arch. Int. Med. 149: 13331337. 11. McLaughlin M., Thomas P., Onorato L, et al. (1988): Use of live virus vaccines in HW-infected children: a retrospective survey. Pediatrics 82: 229-233. 12. Mendez H., Fikrig S., Deforest A., et al. (1988): Response to childhood immunizations in children with human immunodeficiency virus (HIV) infection. 4th International Conference on AIDS, Stockolm 1988. Abstract book, n ° 5109. 13. Nelson K.E., Miotti P., Clements M.L., et al. (1988): The effect of a booster dose of influenza vaccine on antibody response of HW-infected adults. 4th International Conference on AIDS, Stockolm 1988. Abstract book, n ° 5111. 14. Nousbaum J.B., Garre M. and Boles J.M. (1988): Deux manifestation inhabituelles d'une infection par le virus LAV/HIV: BCGite et varicelle pulmonaire. Rev. Pneumol. Clin. 42: 310-311. 15. Onorato LM., Markowitz L.E., Oxtoby M.J. (1988): Childhood immunization, vaccine-preventable diseases and infection with human immunodeficiency virus. Pediatr. Infect. Dis. 6: 588595. 16. Pizzo P.A. (1990): Pediatric AIDS: problems within problems. J. Infect. Dis. 161: 316-325.
3. Borkowsky IV. and Krasinski K. (1987): Residual cellmediated immunity to recall antigens in pediatric AIDS-related disease. Pediatr. Res. 20:292 A.
17. Ragni M. V., Ruben EL., Winkelstein A., et al. (1987): Antibody responses tO immunization of patients with hemophilia with and without evidence of human immunodeficiencyvirus infection. J. Lab. Clin. Med. 109: 545-549.
CDC (1986): Disseminated Mycobacterium bovis infection from BCG vaccination of a patient with acquired immunodeficiency syndrome. MMWR 34: 227-228.
t8. RedfieM R.R., Wright D.C., James W.D., et al. (1987): Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N. Engl. J. Med. 316: 673-676.
4.
215 '
Barbi M. et al.
Eur, J. Epidemiol.
19. Rhoads J.L., Birx D.L., Wright D.C., et aL (1987): Response to vaccination in HIV seropositive subjects. 3rd International Conference on AIDS, Washington 1987. Abstract WP. 110. 20. Special programme on AIDS and expanded programme on immunization (1987): Human immunodeficiency
216
virus infection and routine childhood immunization. Geneva: World Health Organization, WHO/EPI/ GAG/1987/WP 8 rev. 1. 21. Von Reyn CF., Clements C.J., Mann J.M., (1987): Human immunodeficiency virus infection and routine childhood immunization. Lancet, I[: 669-672.
Eur. J. Epidemiol. 0392-2990 March 1992, p. 211-216
Vol. 8, No. 2
OF EPIDEMIOLOGY
ANTIBODY RESPONSE TO INACTIVATED POLIO VACCINE (E-IPV) IN CHILDREN BORN TO HIV POSITIVE MOTHERS M. BARB1.1, M. BARDARE**, C. LURASCHI*, G. ZEHENDER*, M. CLERICI SCHOELLER**, and G. FERRARIS** *Institute o f Virology - Universi~ o f Milan - Via C. P a s c a l 38 - 20133 Milano - Italy. **First Pediatric Clinic - University o f Milan.
Key words: HIV - Children - Immunization - Poliovaccine
In order to evaluate the response to immunization of HIV-infected children we studied the humoral response to an enhanced potency inactivated poliovaccine (E-IPV) of 43 children born of H1V seropositive mothers. All these subjects have been followed for 32 (15-48) months in order to ascertain their infection status. After a course of 2 doses of E-IPV, 88% of children had neutralizing antibody (n.a.) titers > 1:4 to the 3 poliovirus serotypes and 100% to at least 2 polio strains. No statistically significant differences both as rates of n.a. positive subjects and as antibody levels were found between H1V infected children and those who lost HIV antibodies. The poorest response was observed in subjects with full-blown immunodeficiency (CD4 < 1000/mm3, reduced response to PWM). Sixteen children also received a booster dose of vaccine one year after the completion of the primary cycle. Infected and non-infected subjects responded to the same extent with high levels of n.a. to this immunization. Interestingly, the recall dose was also able to induce high n.a. titers in those HIV infected children who showed significant decreases of n.a. titers in the months following the end of the primary cycle.
INTRODUCTION
The weight of pediatric HIV infection, once thought of as a problem restricted only to a few sectors of society, and linked to particular epidemiological situations, is now becoming prevalent throughout the world. The most c o m m o n mode of transmission for pediatric HIV infection if vertical, namely from mother to child. Therefore, the frequency o f this infection is growing, depending on the increase in the rate of w o m e n in their childbearing age who are HIV infected as a result either o f heterosexual transmission or of high risk behaviours (i.e. drug addiction) (16). 1 C o r r e s p o n d i n g author.
211
A serious problem arising from the diffusion of pediatric HIV infection concerns the application of vaccine prophylaxis to children born to seropositive mothers. Indeed, as opposed to the recognized need to give these children routine childhood vaccinations, some doubts have arisen on a theoretical ground both to the harmlessness of antigenic stimulation in subjects potentially infected with HIV and the efficacy of the vaccinations themselves in terms of the extent and duration of the antibody response (7, 15, 19, 21). The only negative data reported so far in the literature involved adults immunised with live tuberculosis and smallpox vaccines (4, 14, 18). Consequently, as far as childhood immunization is concerned, both international (WHO) and national health authorities (7, 20) feel that is better to follow
Barbi M. et aL
Eur. J. Epidemiol.
the normal schedule for all babies who are HIV seropositive at birth. However, Italian as well USA health authorities have decided, on a prudential basis, to suggest the use of the inactivated poliovaccine (Salk type, IPV) rather than the attenuated poliovaccine (Sabin type, OPV) which is used in the general population. In fact, available data on asymptomatic HIV-infected children do not suggest that they are at increased risk of adverse consequences from OPV. The indication of using IPV lies on the possibility that family members may be immunocompromised because of AIDS or HIV infection and may be at increased risk for paralysis from contact with an OPV virus (8). With regards to an evaluation of the immunological efficacy of vaccinating subjects already infected with HIV, in the case of children the situation is complicated by the well-known difficulty of defining the true state of HIV infection of seropositive babies at birth. Indeed, the possible persistence up to the 15th or 18th month of maternal HIV antibodies do not allow the establishment of whether the seropositive state in the first months of life is transitory or whether it is in response to an infection transmitted by the mother. Data in the literature on the consequences of vaccinating such patients are scarce, result from retrospective studies (11), or stem from an examination of clinical records only involving children with symptoms. The aim of the present study was to determine the immunogenicity of polio vaccination in a group of babies who were HIV positive at birth. The antibody response was evaluated in the light of the state of HIV infection of each subject, ascertained during the course of a thorough virological and clinical follow-up.
Polio vaccination An inactivated trivalent vaccine with an enhanced antigenic content (E-IPV) was used. This corresponds to 32, 8 and 40 DU of polioviruses 1, 2 and 3 respectively (IPV-M6rieux, Istituto M6rieux, Italy). Each subject was given 3 intramuscular doses of vaccine at monthly intervals (initial cycle). Sixteen babies received a booster dose about one year after the final dose of the initial cycle.
Samples In order to evaluate the response to vaccination, we examined at least two samples of serum from each baby. One of these, taken before the first injection of vaccine, constituted the basic sample while the second was taken one month after the second inoculation. Further serum specimens were collected from children who received the booster dose. These samples were drawn before and at least one month after the booster.
Serological tests The neutralizing polio antibodies (n.a.) were titrated in microplates on VERO cells. Each serum dilution (from 1:4 to 1:256) was incubated for one hour at room temperature with 100 DC50 of each of the three poliovirus serotypes (attenuated Sabin strains). After the addition of the cells and subsequent incubation for 5 days at 37°C, the results were read. The highest dilution of serum capable of inhibiting the appearance of the viral cytopathic effect was taken as the n.a. titer. The test for antibodies to HIV was carried out by ELISA (Abbot Labs) and Western Blot (Sorin Biomedica).
MATERIALS AND METHODS
Statistical analysis Subjects All children born to HIV seronegative mothers who attended the 1st Pediatric Department since 1988 were enrolled in this study, giving a total of 43 children. The mothers belonged to risk categories, 40 of the 43 women were or had been drug abusers and 3 were partners of HIV seropositive men. The subjects, 17 males and 26 females with a mean age of 8.1 months (range 4-42), were classified at the beginning of E-IPV immunization as follows: P0 26, PI 4 and P2 13. All the children were still seropositive for HIV antibodies at the beginning of the vaccination cycle. Follow-up The subjects studied had checkups every three months for their clinical and immunological condition, as well as a serological ascertainment of their state of HIV infection. 212
Differences between frequencies were compared by means of either the chi-square test with Yates correction or the Fisher's exact method. Geometric mean titer comparisons were performed employing the Student's "t" test. RESULTS
Clinical and immunological evolution At the beginning of the vaccination cycle all 43 children were seropositive for HIV antibodies in ELISA and WB; during the follow-up, which lasted 32 months (range 15-48 months), 26 out of 43 children progressively lost HIV antibodies (group A) at a mean age of 11.6 months (range 4.5-17 months). None of the children belonging to group A ever showed clinical or immunological signs related to HIV infection. They have all been tested for virus isolation
Poliovaccine in HIV+ve children
Vol. 8, 1992
with viral culture and polymerase chain reaction and they were all found negative. The remaining 17 children (group B) showed clinical or immunological signs related to HIV infection before the beginning of the vaccination cycle; in accordance with CDC (Center for Disease Control, Atlanta) criteria (5), 4 were classified as P1B (clinically asymptomatic with immunological alterations) while the other 13 were classified as P2 (clinically symptomatic), even though none of them had AIDS. The immunological features of the 17 HIV-infected children, at the beginning of the vaccination cycle, are represented in Table 1. During the follow-up (the follow-up period was the entire vaccination cycle and included the booster when executed) the clinical status of the 17 children evolved as follow: 5 out of 13 children previously classified as P2 developed full-blown AIDS, and 2 died of pulmonary opportunistic infections. Of the 4 previously classified as P1, 3 became P2 due to the appearance of minor clinical signs related to HIV infection (hepatosplenomegaly and lymphoadenopathy). The immunological situation of the infected children at the end of the vaccination cycle is reported in Table 2. An important involvement of the immunological system marked by frequent polytopic infections was present in 5 children who started treatment with
intravenous immunoglobulins (Endobulin 400 mg/kg) before the beginning of the vaccination cycle.
Response to the polio vaccination The study of humoral response to polio vaccination was performed on all 43 children; 27 of these were studied following the vaccination cycle, 12 were studied after the vaccination cycle and after the booster dose, and 4 were studied exclusively after the booster dose (Figure 1). The response of the HIV seronegative children (group A) was compared with that of HIV-infected subjects (group B). We excluded from this evaluation those HIV-infected babies who had received infusions of gammaglobulin during their initial vaccination cycle and 5 babies (1 infected and 4 seronegative) who, as we subsequently discovered, had already received a dose of OPV. At the end of the first E-IPV cycle all the babies were found to be protected (n.a. titer > 1:4) against at least 2 strains of poliovirus, and 88% of the subjects under study had produced antibodies against all the serotypes. The response frequencies in the two groups of children didn't differ from one another. The extent of the immune response has been ascertained by taking the geometric mean titers (GMT) of n.a. obtained (Table 3).
TABLE 1. - Immunological findings of 17 HIV-infected children before vaccination with E-IPV. Hypergamma globulinemia P1 ( n = 4 )
4/4 (100 %)
CD4/CD8 < 1
CD4 < 2000 /mm 3
0/4 ( 0 % )
0/4
(0%)
Response to PWM reduced 0/4 ( 0 % )
P2 (n = 13)
11/13 (84.6%)
4/13 (30.7%)
5/13" (38.5%)
3/13 (23.0%)
Total
15/17 (88.2%)
4/17 (23.5%)
5/17 (29.4%)
3/17 (17.6%)
* None showed CD4+ lymphocytes < 1000/mm3
TABLE 2. - Immunological evaluation of 17 HIV-infected children at the end of the E-IPV vaccination cycle. Hypergamma globulinemia P1 ( n = 1) P2 (n --- 11)* AIDS ( n = 5)* Total
1/1 (100%)
CD4/CD8 < 1
0/1 (
O)
C D 4 / < 2000 /mm 0/1 (
O)
Response to PWM reduced 0/1 (
O)
11/11 (100%)
9/11 (81.8%)
3/11 (27.2%)
1/11 ( 90 %)
5/5 (100%)
5/5 (100 %)
5/5 (100 %)
5/5 (100 %)
17/17 (100%)
14/17 (82.3%)
8/17 (47.0%)
6/17 (35.2%)
* The mean value of CD4+ lymphocytes globally considered was: in P2 children = l198/mm3 in AIDS children = 530/ram3 213
Barbi M. et al.
TABLE 3.
-
Eur. J. Epidemiol.
Humoral response to the primary cycle of E-IPV immunization and HIV infection status. Response to
Subjects
N
polio 1
polio 2
polio 3
%*
GMT
%*
GMT
%*
GMT
20
100
1 • 27
100
1 • 46
85
1 • 26**
9
100
1 • 29
100
1 • 54
88
1 " 8 **
^
Group A ^
Group B See text
* Rate of children with n.a. titers > 1 : 4 ** P < 0.05
Response to the booster
/I 'm°.l 'm" I J 1
1~1".
A general and marked increase in the titers was observed after administration of the booster dose. For members of both groups, the GMTs then obtained were found to be considerably higher than those obtained after the initial cycle, with the single exception of the response to poliovims 2 in subjects suffering from HIV infection. On the other hand, no significant difference was found between the GMTs obtained from HIV-seronegative children and those who were infected (Table 4).
? ,m°.l/
2
• -
...
3
4
IPV "." s e r u m s = m p l e
Samples t ~
t ~
1+ 2
: 27
subjects
1+2~3+4
: 12
,,
3+4
: 4
',
TABLE 4. - Response to a booster dose of E-IPV and HIV infection status. G M T of neutralizing polio antibodies Subjects
Figure 1. - Time-line of the events over time for the study group.
N
polio 1
polio 2
polio 3
10
1 : 138
1 : 194
1 : 239
6
1 : 81
1 : 64
1 : 144
^
Group A ^
Group B
No significant differences were found in the responses to polio 1 and 2, but the HIV-infected infants responded less well than the uninfected subjects to the type 3 polio virus (p < 0.05). With regards to the 5 cases already vaccinated with OPV, whose basic serum samples already presented andibodies to one or two strains of poliovirus, their response to the other serotypes was found to be comparable to that of the other children.
See text.
Side-effects No side-effects of any sort have been observed. In particular, there were no cases in which the vaccination coincided with clinical and/or immunological deterioration of the subject treated.
Persistence of ~mti-polio antibodies DISCUSSION
With regards to the persistence of antibodies produced after the initial doses of E-IPV, this could be ascertained in only 7 cases. During an interval of 6 months to 1 year from the last vaccination, antibody titers decreased significantly (> 4 times) in the 3 infected babies, but remained unchanged in the 4 subjects belonging to group A. 214
Studies to evaluate the immune response capacity of HIV-infected subjects have indicated that infection by this virus reduces their ability to develop a response against a variety of antigens such as tetanus and diphteria toxoids (2, 3, 19), pneumococcal and influenza vaccines (6, 13, 17), and hepatitis vaccine (10).
Vol. 8, 1992
Poliovaccine in HIV+ve children
With regards to the polio vaccine, however, retrospective studies performed on infected children have shown that both the inactivated and attenuated vaccines are, to some extent, effective. Children vaccinated between 1 month and 15 years earlier had a protective level of antibodies towardsthe poliovirus type 2, in 21 of the 23 cases vaccinated with OPV and in 3 out of 3 cases vaccinated with IPV. The antibody titers were found to be in correlation with the stage of HIV infection (9). In another study the response to three doses of IPV was found to be lower in infected subjects with impaired immunity than that in infected subjects with normal lymphoproliferative responses (1). The present survey has taken into consideration seropositive children whose HIV infection status was unknown because the majority of them were younger than 15 months at the beginning of the study. The good response to vaccination found in HIVinfected children is not surprising if we consider that the immunological system of these babies was not involved when the cycle of polio vaccine was started. The inversion of CD4/CD8 ratio was present in only 23.5% of the children and no one presented a CD4+ lymphocyte number < 1000/ram 3. In fact in the 5 babies with CD4+ < 1000/mm 3and impaired response to PWM, who were treated with IVIG for polytopic infections, the response to vaccine was poor. The significant reduction of n.a. titers detected o n l y in infected subjects needs to be emphasized; nevertheless the good response of the majority of these children to a booster dose suggests that a recall dose in all these children is recommended. How long immunity lasts after the booster dose remains to be seen. Aknowledgements
This study was supported by Regione Lombardia, Convenzione "Indagini diagnostiche ed epidemiologichenel campo delle infezioni da virus HTLV III/LAV'. REFERENCES 1. Bernstein L.J., Ochs H.D., Wedgwood R.J. et aL (1985): Defective humoral immunity in pediatric acquired immune deficiency syndrome. J. Pediatr. 107: 352357. 2. Blanche S., Le Diest F., Fisher A., et al. (1986): Longitudinal study of 18 children with perinatal LAV/HTLV III infection: attempt at prognostic evaluation. J. Pediatr. 109: 965-970.
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19. Rhoads J.L., Birx D.L., Wright D.C., et aL (1987): Response to vaccination in HIV seropositive subjects. 3rd International Conference on AIDS, Washington 1987. Abstract WP. 110. 20. Special programme on AIDS and expanded programme on immunization (1987): Human immunodeficiency
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virus infection and routine childhood immunization. Geneva: World Health Organization, WHO/EPI/ GAG/1987/WP 8 rev. 1. 21. Von Reyn CF., Clements C.J., Mann J.M., (1987): Human immunodeficiency virus infection and routine childhood immunization. Lancet, I[: 669-672.
