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'HIV Exposure Harms Infant Immunity'
Maternal HIV Infection and Antibody Responses Against Vaccine-Preventable Diseases in Uninfected Infants - pdf attached
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Download the PDF here
JAMA Feb 2011
Christine E. Jones, BMBS, MRCPCH; Shalena Naidoo, BSc; Corena De Beer, PhD; Monika Esser, MBChB, MMed (Paed); Beate Kampmann, MBBS, PhD; Anneke C. Hesseling, MD, PhD
"Among South African infants, antenatal HIV exposure was associated with lower specific antibody responses in exposed uninfected infants compared with unexposed infants at birth, but with robust responses following routine vaccination.......In conclusion, our study describes specific antibody responses in mother-infant pairs with and without maternal HIV infection before and after infant vaccination and elucidates mechanisms for reduced responses in HIV-exposed uninfected infants early in life. A significant percentage of non-HIV-infected women also showed insufficient protection. Larger prospective studies are needed to ascertain the relationship between these observed immune responses and clinical end points. Targeted vaccination strategies may be required in HIV-infected women and their infants......To our knowledge, we present the most comprehensive study to date evaluating the association of maternal HIV infection and maternal-specific antibody levels and infant antibody responses to routine World Health Organization Expanded Program on Immunization vaccines. We demonstrate that HIV-exposed uninfected infants have lower specific antibody levels at birth than their non-HIV-exposed peers. Similarly, a smaller proportion of these infants have levels deemed to be protective. We show that this is due to a combination of factors: lower antibody titers to Hib and pneumococcus in HIV-infected pregnant women and reduced transplacental transfer of Hib, pertussis, pneumococcal, and tetanus-specific antibodies. Our data also highlight low levels of specific antibody in HIV-uninfected women with the consequence that half of their infants may not be sufficiently protected against Hib and pertussis early in life. Our findings are consistent with 2 studies in HIV-infected women from Kenya, indicating that maternal HIV is associated with lower tetanus and measles-specific antibody in cord blood and also with reduced placental antibody transfer.4,23 Maternal tetanus-specific antibody levels are lower among HIV-infected women in some studies; inconsistencies observed may be due to differences in vaccination practice during pregnancy.4,7 "
Abstract
Context Altered immune responses might contribute to the high morbidity and mortality observed in human immunodeficiency virus (HIV)-exposed uninfected infants.
Objective To study the association of maternal HIV infection with maternal- and infant-specific antibody levels to Haemophilus influenzae type b (Hib), pneumococcus, Bordetella pertussis antigens, tetanus toxoid, and hepatitis B surface antigen.
Design, Setting, and Participants A community-based cohort study in Khayelitsha, Western Cape Province, South Africa, between March 3, 2009, and April 28, 2010, of 109 HIV-infected and uninfected women and their infants. Serum samples from 104 women and 100 infants were collected at birth and samples from 93 infants were collected at 16 weeks.
Main Outcome Measure Level of specific antibody in mother-infant pairs at delivery and in infants at 16 weeks, determined by enzyme-linked immunosorbent assays.
Results At birth, HIV-exposed uninfected infants (n = 46) had lower levels of specific antibodies than unexposed infants (n = 54) did to Hib (0.37 [interquartile range {IQR}, 0.22-0.67] mg/L vs 1.02 [IQR, 0.34-3.79] mg/L; P < .001), pertussis (16.07 [IQR, 8.87-30.43] Food and Drug Administration [FDA] U/mL vs 36.11 [IQR, 20.41-76.28] FDA U/mL; P < .001), pneumococcus (17.24 [IQR, 11.33-40.25] mg/L vs 31.97 [IQR, 18.58-61.80] mg/L; P = .02), and tetanus (0.08 [IQR, 0.03-0.39] IU/mL vs 0.24 [IQR, 0.08-0.92] IU/mL; P = .006). Compared with HIV-uninfected women (n = 58), HIV-infected women (n = 46) had lower specific antibody levels to Hib (0.67 [IQR, 0.16-1.54] mg/L vs 1.34 [IQR, 0.15-4.82] mg/L; P = .009) and pneumococcus (33.47 [IQR, 4.03-69.43] mg/L vs 50.84 [IQR, 7.40-118.00] mg/L; P = .03); however, no differences were observed for antipertussis or antitetanus antibodies. HIV-exposed uninfected infants (n = 38) compared with HIV-unexposed infants (n = 55) had robust antibody responses following vaccination, with higher antibody responses to pertussis (270.1 [IQR, 84.4-355.0] FDA U/mL vs 91.7 [IQR, 27.9-168.4] FDA U/mL; P = .006) and pneumoccocus (47.32 [IQR, 32.56-77.80] mg/L vs 14.77 [IQR, 11.06-41.08] mg/L; P = .001).
Conclusion Among South African infants, antenatal HIV exposure was associated with lower specific antibody responses in exposed uninfected infants compared with unexposed infants at birth, but with robust responses following routine vaccination.
Infectious diseases account for nearly 6 million deaths worldwide annually in children younger than 5 years.1 Immunization against vaccine-preventable infections therefore remains essential to achieving Millennium Development Goal 4, which is to reduce childhood mortality by two-thirds.2 Before acquisition of immunity, infants are protected by maternal IgG transferred across the placenta. Maternal antibody levels, immunization, infection, and infant gestational age can influence the efficiency of this process.3 ,4,5 ,6,7 Although maternal antibody is essential to protect the infant in the first months of life, maternal-specific antibody can also interfere with the infant's own response to vaccination.8
The high prevalence of maternal human immunodeficiency virus (HIV) in many parts of the resource-poor world, coupled with successful programs to reduce mother-to-child transmission of HIV, has led to increasing numbers of HIV-exposed infants who are not HIV-infected themselves (ie, HIV-exposed infants).9 These infants and children represent a vulnerable group with increased rates of lower respiratory tract infection and meningitis and up to 4-fold higher mortality in the first year of life.10,11 ,12,13 A number of factors are likely to contribute to this increased vulnerability, including socioeconomic factors, but immunological phenomena might also be important.
To design appropriate interventions for these vulnerable infants, it is important to understand how maternal HIV infection influences infant susceptibility to common pathogens. We therefore studied the association of maternal HIV infection with maternal- and infant-specific antibody levels. Because absolute levels of antibody that associate with protection against infection are poorly defined for a number of specific antibodies, we assessed how maternal HIV affects both the magnitude and putative protective levels of these antibodies.
COMMENT
To our knowledge, we present the most comprehensive study to date evaluating the association of maternal HIV infection and maternal-specific antibody levels and infant antibody responses to routine World Health Organization Expanded Program on Immunization vaccines. We demonstrate that HIV-exposed uninfected infants have lower specific antibody levels at birth than their non-HIV-exposed peers. Similarly, a smaller proportion of these infants have levels deemed to be protective. We show that this is due to a combination of factors: lower antibody titers to Hib and pneumococcus in HIV-infected pregnant women and reduced transplacental transfer of Hib, pertussis, pneumococcal, and tetanus-specific antibodies. Our data also highlight low levels of specific antibody in HIV-uninfected women with the consequence that half of their infants may not be sufficiently protected against Hib and pertussis early in life.
Our findings are consistent with 2 studies in HIV-infected women from Kenya, indicating that maternal HIV is associated with lower tetanus and measles-specific antibody in cord blood and also with reduced placental antibody transfer.4,23 Maternal tetanus-specific antibody levels are lower among HIV-infected women in some studies; inconsistencies observed may be due to differences in vaccination practice during pregnancy.4,7
Although it is known that measles, Hib, and pneumococcal vaccine responses are reduced in children infected with HIV, there is a paucity of studies investigating the influence of infant HIV exposure (in the absence of infection) on responses to vaccines.24,25 ,26,27 ,28 We observed an increased vaccine response in HIV-exposed infants to pertussis and pneumococcus compared with HIV-unexposed infants following completion of the immunization schedule. This can be explained by the lower maternally derived antibody levels at birth. Conversely, higher levels of maternal antibody among HIV-unexposed infants at birth corresponded with lower responses postvaccination. Other studies have also reported that maternal antibodies can inhibit infant response to measles, tetanus, whole cell pertussis, and Hib vaccines; this effect varies considerably between different vaccines and studies.8 ,29 The mechanisms through which maternal antibodies inhibit infant responses to vaccination are not fully understood. However, a plausible explanation is that maternal antibodies mask or hide vaccine antigenic epitopes, preventing recognition and binding by infant B cells; a key determinant of infant responses appears to be the maternal antibody-to-vaccine antigen ratio.30
HIV-exposed infants who had missed doses of vaccine before sampling at 16 weeks had higher antibody responses than HIV-unexposed infants to Hib and tetanus, as well as pertussis and pneumococcus. An explanation for this observation is that higher maternal antibodies observed among HIV-unexposed infants may influence the response to the first dose of vaccine but not to subsequent doses. A study in Finland31 reported a similar effect; infants with high levels of maternally derived antibody had lower anti-Hib antibody after the first dose of Hib vaccination, but not after the second dose.
A limitation of our study is enrollment at a single center with a modest number of mother-infant pairs. Sampling was however consecutive and representative of women and infants accessing care in this community setting. We did not have data on maternal vaccination history, due to limitations in recall and documentation. Vaccination records in this setting are typically available for young children only. Women in our study groups had statistically different but clinically comparable ages; therefore, similar maternal vaccination history between groups could be inferred based on the date of the introduction of the universal Expanded Program on Immunization schedule in South Africa (1973).
Although antibody levels can be used to indicate potential susceptibility to infection, some uncertainty remains regarding the functional relevance of a single so-called protective level. In addition, protective levels for collective response to multiple pneumococcal serotypes are unclear and there is a paucity of evidence for defining protective levels for other antibodies such as pertussis.32 Functional assays may give a better assessment of the ability of the immune system to effectively clear a pathogen. Further work to address this aspect is ongoing.
We were unable to correlate antibody levels with long-term vaccine responses or clinical outcomes in the women or infants. However, our data contribute to a potential explanation for the higher morbidity and mortality observed among African HIV-exposed infants. For example, the lower observed pneumococcal-specific antibody among HIV-exposed infants before vaccination might be associated with increased severity of pneumonia observed in this group of infants.12 Our data highlight the need for larger prospective studies to determine whether the lower antibody levels in HIV-exposed infants at birth translate into increased morbidity from vaccine-preventable infections.
Our study results also support the evaluation of novel maternal and neonatal immunization strategies to augment specific antibody responses and potentially prevent infections in infants in early life, particularly in HIV-exposed infants. In view of similar deficiencies also observed in the non-HIV-exposed group, benefits may exist for these infants too.
The implementation of vaccination programs in pregnancy, although resulting in decreased infant and maternal morbidity, is challenging because immunization in pregnancy may impair infant responses to vaccination as a result of increased maternal antibody.21 ,33,34 Evaluation of pneumococcal or pertussis vaccination strategies during pregnancy, or before pregnancy, in settings with high prevalence of HIV however may benefit both mother and child.35,36 ,37,38 ,39 An alternative and feasible strategy is neonatal vaccination. For example, neonatal pertussis vaccination is safe and results in early antibody responses; however, responses to Hib and hepatitis B vaccines may be affected.40 The timing of neonatal vaccinations therefore needs to be carefully considered.41 We recommend evaluation of both maternal and neonatal vaccination strategies, as each has merits and challenges.
In conclusion, our study describes specific antibody responses in mother-infant pairs with and without maternal HIV infection before and after infant vaccination and elucidates mechanisms for reduced responses in HIV-exposed uninfected infants early in life. A significant percentage of non-HIV-infected women also showed insufficient protection. Larger prospective studies are needed to ascertain the relationship between these observed immune responses and clinical end points. Targeted vaccination strategies may be required in HIV-infected women and their infants.
RESULTS
Participant Characteristics
Of 120 eligible mother-infant pairs, 11 mothers declined to participate; therefore, 109 maternal-infant pairs were enrolled (91% participation rate). Of these pairs, 47 mothers (43%) were infected with HIV and 62 (57%) were uninfected. All women testing negative for HIV at their antenatal care registration had a further repeat negative HIV test at delivery. Samples were collected from 105 mothers (96% of the maternal sample; 47 were infected and 58 were uninfected with HIV) at delivery, and from 101 infants (93% of the infant sample; 47 were exposed and 54 were unexposed to HIV) at birth. Sample volumes were insufficient for 4 women and 8 infants. One infant (1%) was determined to be infected with HIV at 4 weeks and was referred for rapid initiation of antiretroviral treatment (mother-infant pair subsequently was excluded from analysis). Follow-up samples were available for 94 infants (87%; 38 were exposed and 55 were unexposed to HIV) at a mean postnatal age of 16.4 weeks (SD, 1.7). One late follow-up sample was excluded from the analysis (collected at 28 weeks after birth). The final analysis was based on samples from 104 women and 100 infants collected at birth and samples from 93 infants collected at 16 weeks.
Characteristics of the study cohort are shown in Table 1. All HIV-infected women chose exclusive formula replacement feeding. The mean (SD) CD4 count among the HIV-infected women was 474 (252) cells/μL and the median (IQR) viral load was 800 (357-6000) copies/mL. Seven women had CD4 counts of less than 200 cells/μL; 3 of these were taking highly active antiretroviral treatment at enrollment and 4 were referred to commence highly active antiretroviral treatment following delivery.
Infant-Specific Antibody Responses at Birth
At birth, HIV-exposed uninfected infants had significantly lower specific antibody levels compared with unexposed infants to Hib (0.37 [IQR, 0.22-0.67] mg/L vs 1.02 [IQR, 0.34-3.79] mg/L; P < .001), pertussis (16.07 [IQR, 8.87-30.43] FDA U/mL vs 36.11 [IQR, 20.41-76.28] FDA U/mL; P < .001), pneumococcus (17.24 [IQR, 11.33-40.25] mg/L vs 31.97 [IQR, 18.58-61.80] mg/L; P = .02), and tetanus (0.08 [IQR, 0.03-0.39] IU/mL vs 0.24 [IQR, 0.08-0.92] IU/mL; P = .006) (Figure 1).
These lower levels observed in HIV-exposed infants at birth corresponded with a lower proportion of HIV-exposed infants with levels considered to be protective against Hib (17% vs 52%; P < .001), pertussis (24% vs 57%; P = .001), tetanus (43% vs 74%; P = .002), and hepatitis B (21% vs 54%; P = .01).
In a multiple linear regression model for factors associated with magnitude of specific antibody response at birth, HIV exposure remained associated with reduced Hib titers (unstandardized regression coefficient [b] = 0.49; SE, 0.12; P < .001), pertussis (b = 0.38; SE, 0.08; P < .001), pneumococcus (b = 0.24; SE, 0.10; P = .01), and tetanus (b = 0.52; SE, 0.16; P = .002) levels (eTable 1). There was no association with maternal age, gravidity, housing structure, infant sex or birth weight for Hib, pneumococcus, and tetanus levels, but increased maternal age was associated with higher pertussis-specific antibody titers (b = 0.02; SE, 0.01; P = .03) (eTable 1).
Maternal-Specific Antibody Responses
To investigate the mechanisms associated with infant response, we measured specific maternal antibody levels in parallel. HIV-infected women had lower specific antibody levels than uninfected women to Hib (0.67 [IQR, 0.16-1.54] mg/L vs 1.34 [IQR, 0.15-4.82] mg/L; P = .009) and pneumococcus (33.47 [IQR, 4.03-69.43] mg/L vs 50.84 [IQR, 7.40-118.00] mg/L; P = .03). No differences were observed for pertussis (22.07 [IQR, 12.48-29.67] FDA U/mL vs 23.64 [IQR, 12.87-54.68] FDA U/mL; P = .26) or tetanus (0.09 [IQR, 0.03-0.33] IU/mL vs 0.15 [IQR, 0.06-0.67] IU/mL; P = .12) between HIV-infected and uninfected women. In a multiple regression model for factors associated with level of maternal-specific antibody response, maternal HIV infection remained associated with low Hib and pneumococcal antibody levels; however, there was no significant association with maternal age, gravidity, or housing structure for any of the specific antibody responses (eTable 1).
HIV-infected women were less likely to have anti-Hib antibodies levels considered to be protective (35% vs 59%; P = .02). The proportion of women with protective antibody levels against pertussis (24% vs 38%; P = .14), tetanus (47% vs 64%; P = .11), or hepatitis B (26% vs 33%; P = .52) was similar in HIV-infected and HIV-uninfected women. The overall proportion of all women with protective antibody levels was low for pertussis (32%), tetanus (41%), and hepatitis B (30%).
In HIV-infected women, CD4 count was positively correlated with the level of antibody to pertussis (r = 0.31; P = .04), pneumococcus (r = 0.33; P = .03), and tetanus (r = 0.37; P = .01), but not with Hib (r = -0.07; P = .63) (eTable 2). There was no correlation between maternal HIV viral load and any specific antibody level (eTable 2).
In HIV-infected women and their infants, the correlation between maternal- and infant-specific antibody responses were statistically significant for Hib (r = 0.91; P < .001), pertussis (r = 0.78; P < .001), pneumococcus (r = 0.86; P < .001), and tetanus (r = 0.95; P < .001). In HIV-negative women, the correlation between maternal and infant responses were also statistically significant for Hib (r = 0.95; P < .001), pertussis (r = 0.89; P < .001), pneumococcus (r = 0.80; P < .001), and tetanus (r = 0.93; P < .001).
Association of Maternal HIV With Placental Transfer of Specific Antibody
The proportion of maternal-specific antibody transferred across the placenta to infants was significantly reduced among HIV-infected women and their infants. Using infant:maternal antibody ratios as a proxy for placental transfer, HIV-infected women had significant reductions in placental transfer of 23% for Hib, 40% for pertussis, and 27% for tetanus-specific antibodies compared with HIV-uninfected women, with a trend toward a reduction in placental transfer of pneumococcal specific antibodies (Table 2). Among HIV-infected women, there was no association between maternal CD4 count or viral load and placental transfer (eTable 2).
Specific Vaccine-Induced Antibody Responses in Infants at 16 Weeks
In stratified analysis for infants who had received 1, 2, or 3 doses of DTP-Hib vaccine (n = 6, 22, and 65, respectively), there was no difference in antibody levels between infants who had received 1 or 2 doses (eTable 3); these groups were therefore combined for further analysis. Similarly, data were combined for infants who had received 1 or 2 doses of pneumococcal capsular polysaccharide (n = 15 and 34, respectively). There was no statistical difference in the proportion of HIV-exposed and HIV-unexposed infants who received fewer than 3 doses of DTP-Hib vaccine (25% vs 16%; P = .31) or fewer than 2 doses of pneumococcal capsular polysaccharide (20% vs 49%; P = .06) before the 16-week sampling.
Despite initially lower titers at birth, HIV-exposed uninfected infants mounted robust responses following vaccination. In the group that received all 3 scheduled doses of DTP-Hib vaccine, HIV-exposed infants had significantly higher responses to pertussis (270.1 [IQR, 84.4-355.0] FDA U/mL vs 91.7 [IQR, 27.9-168.4] FDA U/mL; P = .006) than unexposed infants did (Figure 2), but had similar responses to Hib and tetanus. HIV-exposed infants also had higher levels of pneumococcal-specific antibody than HIV-unexposed infants did (47.32 [IQR, 32.56-77.80] mg/L vs 14.77 [IQR, 11.06-41.08] mg/L; P = .001). Among infants who had received only 1 or 2 doses of DTP-Hib vaccine, responses were higher in the HIV-exposed infants than unexposed infants to Hib (6.46 [IQR, 1.74-9.29] mg/L vs 0.54 [IQR, 0.24-4.10] mg/L; P = .02), pertussis (81.16 [IQR, 38.64-195.40] FDA U/mL vs 11.60 [IQR, 5.30-39.42] FDA U/mL; P < .001), and tetanus (1.86 [IQR, 0.51-2.21] IU/mL vs 0.50 [IQR, 0.10-0.93] IU/mL; P = .01) (Figure 2).
The fold increase in antibody level before and after vaccination was significantly higher in the HIV-exposed infants than in the HIV-unexposed infants for Hib (21.15-fold increase [IQR, 6.84-118.40] vs 2.97-fold increase [IQR, 0.71-16.69]; P = .007), pertussis (9.51-fold increase [IQR, 2.80-24.25] vs 2.16-fold increase [IQR, 0.41-6.84]; P = .002), and pneumococcus (2.06-fold increase [IQR, 0.96-5.70] vs 0.31-fold increase [IQR, 0.26-1.04]; P < .001). There was no difference in the fold-increase at prevaccination and postvaccination between the 2 groups for tetanus-specific responses (14-fold increase [IQR, 3.26-116.20] vs 12-fold increase [IQR, 2.8136.35]; P = .54).
Figure 3 shows prevaccination and postvaccination antibody levels for individual infants. Infants with the lowest levels of anti-Hib, pertussis, pneumococcal, and tetanus-specific antibodies showed the greatest vaccine responses at 16 weeks. HIV exposure was associated with a greater magnitude of change between birth and 16 weeks.
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