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Effect of Placental Malaria and HIV Infection on the Antibody Responses to Plasmodium falciparum in Infants

  1. Renée M. Ned1,a,
  2. April E. Price1,a,
  3. Sara B. Crawford2,3,a,
  4. John G. Ayisi5,
  5. Anna Maria van Eijk5,
  6. Juliana A. Otieno6,
  7. Bernard L. Nahlen7,
  8. Richard W. Steketee1,
  9. Laurence Slutsker1,
  10. Ya Ping Shi1,
  11. David E. Lanar4 and
  12. Venkatachalam Udhayakumar1
  1. 1Malaria Branch, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Chamblee, Georgia
  2. 2Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Chamblee, Georgia
  3. 3Atlanta Research and Educational Foundation, Decatur, Georgia
  4. 4Walter Reed Army Institute of Research, Silver Spring, Maryland
  5. 5Kenya Medical Research Institute, Kisumu, Kenya
  6. 6New Nyanza Provincial Hospital, Kisumu, Kenya
  7. 7Roll Back Malaria, World Health Organization, Geneva, Switzerland
  1. Reprints or correspondence: Dr. Venkatachalam Udhayakumar, Malaria Branch, Centers for Disease Control and Prevention, 4770 Buford Hwy., MS F-12, Chamblee, GA 30341 (vxu0{at}cdc.gov).

  • ↵a Present affiliations: McKing Consulting Corporation, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, Georgia (R.M.N.); University of California, San Francisco (A.E.P.); Valparaiso University, Valparaiso, Indiana (S.B.C.).

 
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Abstract

Background. Placental malaria (PM) and maternal infection with human immunodeficiency virus (HIV) type 1 have been shown to affect infant morbidity and immune responses to Plasmodium falciparum. We studied the effects of PM and HIV infection on the antimalarial antibody responses and morbidity outcomes of infants throughout the first year of life.

Methods. A total of 411 Kenyan infants who were born to mothers who were singly or dually infected with PM and/or HIV had their levels of immunoglobulin G antibody to 6 P. falciparum antigens/epitopes (apical membrane antigen-1, erythrocyte-binding antigen-175; liver-stage antigen-1 [LSA-1], circumsporozoite protein [CSP], merozoite surface protein-2, and rhoptry-associated protein-1 [RAP-1]) and to tetanus toxoid (TT) tested using enzyme-linked immunosorbent assay.

Results. PM had little effect on the antibody responses of infants, whereas maternal HIV infection resulted in decreased levels of antibody to LSA-1, CSP, and RAP-1 epitopes at birth, compared with the absence of PM and maternal HIV infection (P < .0063). Levels of antibodies to TT were significantly reduced in infants born to mothers coinfected with HIV and PM, compared with the levels noted in infants born to HIV-negative mothers (P < .0003). In HIV-infected infants, levels of antibody to TT were reduced, but levels of antibody to malarial antigens were not. Antimalarial antibody levels were positively associated with malaria-related morbidity outcomes.

Conclusion. Infant HIV infection and maternal coinfection with HIV and PM negatively influence antibody responses to TT, but not those to malarial antigens, in infants. Antimalarial antibodies rarely showed protective associations with morbidity in infants and were more often a marker for malaria exposure and risk of infection.

In malaria-endemic regions, pregnant women have a higher risk of malaria than do nonpregnant women, and parasites can sequester in the placenta. This condition, known as “placental malaria” (PM), is associated with maternal anemia, intrauterine growth retardation, preterm delivery, and low birth weight [1]. Recent studies have also shown that PM increases the risk for parasitemia and anemia among infants [2–4], and this increased risk may be further influenced by the gravidity of the mother [5].

In sub-Saharan Africa, HIV-1 infection has also become widespread, and coinfection with HIV-1 and malaria leads to complex biological interactions [6, 7]. In pregnant women, HIV-1 infection increases the risk of acquiring high-density Plasmodium falciparum infection [7, 8]; however, the effects of maternal coinfection with HIV-1 and PM on infants are unclear. There have been conflicting results regarding the effect of PM on mother-to-child transmission of HIV-1 [9–11]. However, PM has been shown to be a risk factor for postneonatal mortality among infants born to HIV-infected women [12, 13], although, in other studies, including findings noted for the same cohort evaluated in the present study, this association was not observed [14, 15].

In the absence of HIV-1 infection, PM affects cellular immunity in infants, diminishing production of interleukin (IL)-12 and interferon (IFN)-γ and affecting T helper cell type 1/type 2 priming of neonatal lymphocytes [16]. We previously reported that PM decreased antibody responses to some, but not all, malarial epitopes tested in infants [4]. Maternal HIV infection itself has been shown to adversely affect the development of antibody responses to various antigens and vaccines in cord blood, newborns, and infants [17–21]. With regard to malaria, maternal HIV infection has been associated with reduced cord blood levels of antibodies to erythrocyte-binding antigen (EBA)-175 and circumsporozoite protein (CSP) [20].

In the present study, we investigated how maternal HIV infection and PM influenced the development of antibody responses to natural infection with P. falciparum in infants, as well as how the development of antibody responses was associated with infant morbidity.

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Patients and Methods

Patients and sample collection. On a monthly basis, plasma samples were obtained from children who participated in a longitudinal cohort study assessing the interaction between malaria and HIV-1 infection in pregnant women and their infants [9, 22]. The study was conducted at the Nyanza Provincial General Hospital in Kisumu, western Kenya. Enrollment lasted from June 1996 through August 2000, and infant follow-up ended in August 2001. Informed written consent was obtained from the parents or caretakers of all infants. Women who had P. falciparum parasites detected microscopically in thick blood films made using placental intervillous blood were considered to be positive for PM. Details regarding enrollment, standard laboratory procedures used for HIV testing, determination of hemoglobin levels, and patient follow-up have been reported elsewhere [9, 15]. For the present study, mothers were classified as belonging to 1 of 4 infection groups: PM-negative, HIV-negative mothers (i.e., uninfected mothers); PM-positive, HIV-negative mothers; PM-negative, HIV-positive mothers; and PM-positive, HIV-positive mothers (i.e., coinfected mothers). Infants born to mothers in any of these infection groups were included in analyses if they remained in the study until ≥5.5 months of age and if ≥6 observations were made during the 12 months of follow-up reviewed. All eligible infants born to HIV-negative mothers (both PM-negative and PM-positive mothers) and all those born to coinfected mothers were included. Because of the excess of PM-negative, HIV-positive mothers enrolled in the study, all HIV-positive children and a subset of their HIV-negative children (who were matched on the basis of their birth date ± 2 weeks) were included. Patient characteristics are presented in tables 1 and 2.

Figure 1
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Figure 1

Longitudinal antibody responses in infants, stratified by the infection status of the mother. Serum samples collected from 411 infants at birth and then monthly throughout the first year of life were analyzed by ELISA for the total levels of IgG antibodies to 7 Plasmodium falciparum antigens and to tetanus toxoid (TT). The raw mean antibody levels were normalized by calculating the log10 value of the antibody response value + 1 and were stratified according to the infection status of the mother. AMA-1, apical membrane antigen-1; EBA-175, erythrocyte-binding antigen-175; LSA-1, liver-stage antigen-1; neg, negative; PL720, peptide epitope of circumsporozoite protein; PL1210, peptide epitope of LSA-1; PL1250, peptide epitope of merozoite surface protein-2; PL1487, peptide epitope of rhoptry-associated protein-1; PM, placental malaria; pos, positive.

Figure 2
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Figure 2

Longitudinal antibody responses in HIV-negative and HIV-positive infants. Serum samples collected from infants at birth and then monthly throughout the first year of life were analyzed by ELISA for the total levels of IgG antibodies to 7 Plasmodium falciparum antigens and to tetanus toxoid (TT). The raw mean antibody levels were normalized by calculating the log10 values of the antibody response value + 1 and were stratified according to the infection status of the infant. AMA-1, apical membrane antigen-1; EBA-175, erythrocyte-binding antigen-175; LSA-1, liver-stage antigen-1; PL720, peptide epitope of circumsporozoite protein; PL1210, peptide epitope of LSA-1; PL1250, peptide epitope of merozoite surface protein-2; PL1487, peptide epitope of rhoptry-associated protein-1.

Table 1
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Table 1

Characteristics of mothers and their infants included in the analysis of placental malaria (PM) and maternal HIV infection status and the antibody responses of infants.

Table 2
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Table 2

Characteristics of infants included in the study, according to the HIV infection status of the child.

Antigens and peptides. We selected antigens and epitopes that would be broadly recognized by human antibodies to malaria and that would serve simply as markers of the immune response. The following antigens derived from various P. falciparum proteins were used: liver-stage antigen-1 (LSA-1), which includes the N-terminus, 2 repeats, and the C-terminus of the LSA-1 3D7 strain [23]; EBA-175 (region II of the 3D7 strain) [24]; and apical membrane antigen-1 (AMA-1; the ectodomain of the FVO strain) [25]. Peptides representing conservative epitopes from the preerythrocytic-stage antigens CSP (PL720: NANPNANPNANPNANPNANP) [26] and LSA-1 (PL1210: AKEKLQEQQSDLEQERLAKEKLQEQQSDLEQERL) [26] and from erythrocyte-stage antigens merozoite surface protein (MSP)-2 (PL1250: NSVGANAPNADTIASGSQRS) (Z. Zhou, unpublished data) and rhoptry-associated protein-1 (RAP-1) (PL1487: FFKEMRIQYAKLINIRYRSH) (Z. Zhou, unpublished data) were also used. The immunogenicity of PL720 and PL1210 has been demonstrated in this study population [26]. Peptides PL1250 and PL1487 were chosen because they demonstrated a high frequency of positive antibody responses among several overlapping peptides from MSP-2 and RAP-1 antigens, respectively, that were tested in this population (Z. Zhou, unpublished data). Tetanus toxoid (TT; Connaught Laboratories) was used as a control antigen to test for underlying differences in the ability to mount antibody responses.

Protein antigens (supplied by D. E. Lanar) were >98% pure. Peptides were synthesized at the Biotechnology Core Facility at the Centers for Disease Control and Prevention. They were 80%–90% pure and were used without further purification.

Antibody assays. Total IgG antibody levels were measured using a standard ELISA [4]. Flat-bottom microtiter Immulon-2 HB plates (ThermoLabsystems) were coated with 100 µL of antigen or peptide per well in 0.01 mol/L PBS (pH 7.2) overnight at 4°C. EBA-175 and LSA-1 were coated at a concentration of 0.25 µg/mL; AMA-1, at 0.5 µg/mL; and TT, at 0.1 µg/mL. All peptides were coated at a final concentration of 5 µg/mL. After incubation overnight, plates were washed 3 times with PBS/0.05% Tween-20 (PBST) and then were blocked with 3% bovine serum albumin (BSA)/PBST for 1 h at room temperature. Plates were washed again 3 times with PBST. Serum samples collected from infants were diluted in 3% BSA/PBST/0.1% NP-40 at 1:100 for peptides, at 1:200 for LSA-1, and at 1:800 for AMA-1, EBA-175, and TT. Serum samples were added in duplicate at 100 µL/well and were incubated overnight at 4°C. Plates were washed 4 times with PBST and were incubated with 100 µL of peroxidase-conjugated goat anti-human IgG antibodies (Southern Biotechnology Associates) diluted at 1:4000. After incubation for 1 h at room temperature, plates were washed 5 times with PBST and were developed with 100 µL of 3,3′,5,5′-tetramethylbenzidine (KPL Laboratories) per well for 10 min. Reactions were stopped using 1 mol/L phosphoric acid.

Plates were read at 450 nm with a SpectraMax 340 ELISA reader (Molecular Devices) and SOFTmax PRO software (Molecular Devices). Human negative control plasma samples (obtained from North American adults with no history of travel to malarious regions) were included on each plate. Positive control plasma, which consisted of pooled high-titer serum samples obtained from clinically immune Kenyan adults, was serially diluted 2-fold, starting at 1:200, to generate a standard curve. Each dilution of the standard was assigned an antibody unit value, and the relative antibody unit in each test serum sample was determined by comparison. Infant serum samples for which the optical density values were very high were run at higher dilutions (up to 1:204,800) until the values were within the linear portion of the standard curve.

Statistical analysis. Antibody responses were log normalized (the log10 value of the antibody response value + 1) and were modeled against the infection status of the mother, by use of a mixed model of the log-transformed values. For antibody responses at birth, the models controlled for birth weight (<2500 g), gestational age (<37 months), HIV infection status of the child, gravidity of the mother (primigravid, secundigravid, or multigravid), and season of malaria transmission (i.e., rainy or postrainy season). For antibody responses throughout the first year of life, the models also controlled for antibody levels at baseline, age of the child, and an indicator for the first 4 months of life (age <4 months, hereafter referred to as a “4-month indicator”). Because the rate of change in the log antibody levels was thought to differ depending on the age of the child (<4 months or ≥4 months of age), an interaction between the age of the child and the 4-month indicator was also included. Interactions between the infection status of the mother, the infection status of the child, and the 4-month indicator were assessed for statistical significance. A similar analysis was conducted to report the difference in mean log antibody levels according to the infection status of the child. The correlation between the longitudinal responses for each subject was incorporated using a compound symmetric covariance function. All of the figures and tables reflect the difference in the means, where pairwise comparisons of the means according to the infection status of the mother or the infection status of the child were performed using a simulated adjustment for multiple comparisons. P values were compared with an α level of 0.0063, which reflects a Bonferroni adjustment of the traditional α level of 0.05 for the 8 antigens of interest.

Each of 7 morbidity events was modeled against the antibody response by use of Poisson regression. These models controlled for antibody levels at baseline, birth weight, gestational age, age of the child (expressed in months), the 4-month indicator, interaction of the age of the child and the 4-month indicator, HIV infection status of the child, infection status of the mother, gravidity of the mother, and season of malaria transmission. For those morbidity events that were not defined by parasitemia, the models also controlled for the presence of parasitemia. Interactions were assessed between antibody response and the age of the child and the infection status of the child, and results are reported according to these variables, where statistically significant. The correlation between measurements for the same subject was incorporated using generalized estimating equations with a compound symmetric correlation matrix, to produce empirically corrected standard errors for the parameter estimates. All of the P values presented for morbidity outcomes are unadjusted P values. An α level of 0.0009 was used to determine statistical significance, reflecting a Bonferroni adjustment for the 8 antigens and 7 measurements of morbidity assessed.

Survival analysis was also conducted to examine the effects of the baseline and longitudinally measured antibody levels on the time to the first morbidity event. Cox regression was used to explore these associations, controlling for the same variables listed in the previous paragraph. Interactions associated with the age of the child and the HIV infection status of the child were explored for both the baseline and longitudinally measured antibody levels. P values are unadjusted, but they were compared with an α level of 0.0009, to determine significance. All analyses were performed using SAS software (version 9.1; SAS Institute). Because of the large number of models considered for the Poisson and Cox regressions, only significant results at the Bonferroni-adjusted levels are presented for these analyses.

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Results

Patient characteristics. The profile of patient characteristics, as summarized by the infection status of the mother, is presented in table 1. As expected, higher proportions of PM-positive mothers were primigravid (P = .0007). There were significant differences in the percentage of infant follow-up visits associated with the infection status of the mother, with regard to visits with mild anemia (hemoglobin level, <11 g/dL), moderate anemia (hemoglobin level, <8 g/dL), parasitemia, and parasitemia with mild anemia. Infants born to mothers with PM, regardless of the maternal HIV infection status, had increased risks for these morbidity outcomes, compared with infants born to uninfected mothers.

Basic descriptive statistics based on the HIV infection status of the child are presented in table 2. During the 12 months of follow-up reviewed, the mean number of follow-up visits and the average age at the last visit were slightly lower than the same data for HIV-negative infants. HIV-positive children had a higher percentage of visits with fever (temperature >37.5°C) and mild anemia; however, the percentage of visits with more specific malaria-related outcomes did not differ between HIV-positive and HIV-negative children.

The influence of maternal HIV infection and PM status on the antibody responses of infants. To assess the influence of maternal infection on infant antibody responses over the 12-month period, the unadjusted mean antibody levels were stratified according to the infection status of the mother. As shown in figure 1, infants born to HIV-1-positive, PM-negative mothers tended to have lower mean levels of antibodies to AMA-1, EBA-175, LSA-1, PL720, and PL1210 at birth than did infants born to mothers in one of the other groups. The statistical significance of the differences in the mean levels of antibodies between different groups is presented in table 3. At birth, levels of antibody to all antigens except PL1250 were similar in infants born to PM-positive, HIV-negative mothers and those born to uninfected mothers. At birth, infants born to PM-negative, HIV-positive mothers had lower levels of antibody to LSA-1, PL720, PL1210, and PL1487 than did infants born to uninfected mothers, and they had lower levels of antibody to AMA-1, LSA-1, PL1210, and PL1487 than did coinfected mothers (P < .0063, for all). In contrast, infants born to coinfected mothers had significantly lower levels of TT antibodies, compared with infants born to HIV-negative mothers (both PM-negative and PM-positive mothers) (P < .0063) (table 3). Comparisons of antibody levels according to the infection status of the mother were not affected by the HIV infection status of the child, and antibody levels were not associated with the maternal viral load or the CD4 T cell count (data not shown).

Table 3
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Table 3

Influence of maternal infection status on infant antibody responses at birth.

In analyses of maternal infection status and the mean antibody responses of infants throughout the first year of life, very few significant differences were found (see table A1 in the appendix, which is available only in the electronic version of the Journal). However, infants born to coinfected mothers had significantly lower levels of TT antibodies in the first 4 months of life, compared with infants born to HIV-negative mothers, regardless of PM status (P < .0001.

Antibody responses, by HIV infection status of the infant. The unadjusted mean antibody levels over time, as stratified by the HIV infection status of the child, are presented in figure 2 . At birth, HIV-positive infants had significantly lower levels of antibodies to TT (mean difference [±SE], 0.37±0.13; P = .0035) but not to any of the malarial antigens (data not shown). Anti-TT antibody levels were also decreased throughout the first year of life in HIV-positive infants, compared with HIV-negative infants (P < .0001) (table 4). Interestingly, mean levels of antibody to PL1487 were significantly higher in HIV-positive children than in HIV-negative children during the first year of life (P < .0001) (figure 2 and table 4). However, there were no other significant differences in mean antibody levels associated with the HIV infection status of the child.

Table 4
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Table 4

Comparison of antibody responses between HIV-negative and HIV-positive infants in the first year of life.

Association between antibody responses and infant morbidity. There were numerous significant associations between the antibody levels of infants and concurrent morbidity, all of which showed that increased risk was associated with an increased antibody response (P < .0009) (see table A2 in the appendix, which is available only in the electronic version of the Journal). We reasoned that the level of antibodies noted at a previous study visit may be a better predictor of morbidity outcomes, because it is this antibody response that could potentially prevent or delay a new case of malaria. However, no protective associations were found between antibody levels at a previous visit and the morbidity indicators tested (data not shown).

We also examined whether there was any delay in the first occurrence of a morbidity outcome in relation to the antibody response of infants (table 5). Throughout the first year of life, increased antibody responses to AMA-1 (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.35–0.62) and EBA-175 (HR, 0.46; 95% CI, 0.33–0.65) delayed the first occurrence of mild anemia (P < .0001, for both). However, throughout the first year of life (time varying), high levels of antibody to many of the antimalarial antigens were associated with a shorter time to a first morbidity event (HR, >1) (P < .0009).

Table 5
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Table 5

Time to first morbidity outcome, by infant antibody response.

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Discussion

We report an increase in malaria-associated morbidity among infants born to PM-positive mothers, as demonstrated in other studies [2–5]. An increased percentage of visits for fever and for mild anemia—but not for more-specific malaria-related outcomes—was also noted for HIV-infected infants during the 12-month study, consistent with recent reports from Kenya [3, 27].

We show that the PM status and maternal HIV-1 infection status influence infant antibody responses to malarial antigens to varying degrees. PM alone did not affect the antibody levels of infants to malarial antigens at birth (except for PL1250, an MSP-2 epitope) or during the 12 months of follow-up. However, in a previous study, we reported that maternal PM decreased antibody responses in infants 4–12 months of age, for at least 4 of 7 P. falciparum epitopes tested (including peptide epitopes from CSP, EBA-175, and RAP-1) [4]. This difference may be the result of the considerably larger sample size in the current study and the different statistical models and epitopes that were used. It is our speculation that there probably is epitope-specific regulation of immune responses due to maternal exposure to malaria, a finding consistent with recent results demonstrating that maternal malaria exposure could lead to either T cell sensitization or to T cell tolerance to MSP-1 antigens in infants [28]. Although other studies have also documented that maternal exposure to malaria can lead to prenatal sensitization to malaria antigens, as indicated by the presence of malaria-specific T cell and antibody responses in cord blood cells [29–32], we suggest that maternal exposure to malaria modulates the infant immune system in distinct ways. This modulation depends on several factors, which include fetal age when the exposure occurred, antigenic load, the cytokine environment, and the nature of the antigen. Interestingly, among HIV-1-infected children, there was no apparent difference in the infants' antibody response due to the PM status of the mother (data not shown).

Infants born to mothers with HIV-1 infection but without PM had reduced antibody responses to some malarial antigens at birth, compared with infants born to uninfected mothers. However, anti-TT antibody levels were not affected. This may reflect decreased levels of specific antimalarial antibodies in HIV-positive mothers or decreased maternal transfer of antibodies in mothers with HIV. The results of a previous study conducted in this population showed evidence for both mechanisms. It was found that maternal HIV-1 infection resulted in reduced prevalence and concentration in maternal blood of antibodies to 2 of the 9 P. falciparum antigens/peptides tested: CSP repeat (NANP)5 and MSP-2 [20]. Maternal HIV-1 infection also negatively affected the maternal transfer of antibodies to this CSP repeat epitope, but not to other antigens, including tetanus [20]. However, a recent study demonstrated that maternal HIV infection decreased tetanus antibody levels in newborns by 52% [33]. Other studies have reported that HIV-1-infected mothers have lower levels of antibodies to measles and demonstrate less maternal transfer of antimeasles antibodies than do HIV-negative mothers [18, 19, 34].

Interestingly, infants born to mothers coinfected with HIV-1 and PM had a significant reduction in TT antibody levels, but not in malarial antibody levels, at birth and in the early months of life, compared with infants born to HIV-negative mothers (both PM-negative and PM-positive mothers). As mentioned previously, this could be the result of lower levels of tetanus antibody and/or poor transfer of tetanus-specific antibodies in coinfected mothers. This possibility suggests that coinfection may significantly affect the development of antibodies to T cell-dependent antigens, such as tetanus vaccine. Because malaria can induce antibody responses without classical T cell help [35], this may explain why maternal coinfection has less influence on infant malarial antibody responses.

HIV infection in infants also caused significant reductions in TT antibody responses at birth and during the first year of life. In contrast, HIV-1-infected infants demonstrated higher levels of antibodies to PL1487 (an RAP-1 epitope) throughout the first year of life (but not at birth), compared with HIV-1-negative infants. In previous studies, HIV-1-infected infants were shown to have reduced levels of antibodies to pneumococcal conjugate vaccine [36] and to hepatitis B vaccine [37]. From these results, it appears that HIV-1 infection does not lead to generalized immunosuppression against malaria in infants; instead, it selectively modulates antibody responses to some antigens. Once again, this could be a result of the T cell independence of some malarial antibody responses [35]. It is important to note that the death rate among HIV-1-infected infants in this cohort was higher than that among HIV-uninfected infants [15], and, therefore, the former group tended to contribute slightly fewer months of follow-up to the study.

Overall, there were few significant protective associations between infant malarial antibody levels and malaria-associated morbidity. On the contrary, there were numerous significantly increased risks of morbidity associated with increased antibody responses. The lack of protective associations for most of the morbidity outcomes may be due to the small number of events for some of the measurements of morbidity, qualitative differences in the antimalarial responses of the infants, or the fact that these antibodies are not relevant for protection. Although several conserved epitopes are present among the antigens/peptides tested in the current study, if the development of antibody responses occurred in a T cell-independent manner, less protective, low-affinity antibodies may have been generated. One important limitation of the current study is that we did not perform functional antibody assays. Therefore, the conclusions regarding protective associations need to be carefully considered. It is important to point out that, for many of the epitopes tested, there was a decrease in antibody responses during the first year of life, compared with antibody levels noted at birth. In other studies, maternally derived antibodies to CSA [38] and to IgG subclass antibodies to P. falciparum schizont extract, Pf155/RESA, and MSP-1 (19 kD) [39] have been shown to be positively correlated with parasitemia rates or density in infants. There is convincing evidence that antibodies to MSP-1 are protective against clinical malaria in infants and older children, but there is no consensus regarding other malaria-specific antibodies [40, 41]. Overall, there appears to be little protection from parasitemia or clinical malaria in infants because of passively acquired or infant-produced antibodies [4, 26, 38–40].

In summary, maternal coinfection with HIV and PM modulates antibody responses to tetanus vaccine and to some malarial antigens at birth. HIV-1 infection in infants reduced antibody responses to tetanus vaccine but not to malarial antigens. However, maternal infection status and infant antimalarial antibody responses were associated with an increased risk for a number of malaria-related morbidity outcomes. As hypothesized in previous studies, antimalarial antibodies, as measured by nonfunctional assays, may be markers for malaria exposure and, subsequently, risk of infection, rather than being protective against parasitemia or clinical malaria in the infant.

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Acknowledgments

We thank all of the volunteers for participating in this study and the field staff for their support. We also thank the Kenya Medical Research Institute and its director for providing permission to publish this study.

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Footnotes

  • Potential conflicts of interest: none reported.

  • The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

  • Financial support: Atlanta Research and Educational Foundation and Centers for Disease Control and Prevention (CDC)/Division of HIV and AIDS Prevention (grant CDC IAA 98FED09325). R.M.N. was supported by an appointment to the Emerging Infectious Diseases (EID) Postdoctoral Fellowship Program, and A.E.P. was supported by an appointment to the EID Training Fellowship Program; both programs were administered by the Association of Public Health Laboratories and funded by the CDC.

  • Received January 28, 2008.
  • Accepted June 25, 2008.
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References

  1. ↵
    1. Steketee RW,
    2. Nahlen BL,
    3. Parise ME,
    4. Menendez C
    . The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg 2001;64:28-35.
    Abstract/FREE Full Text
  2. ↵
    1. Le Hesran JY,
    2. Cot M,
    3. Personne P,
    4. et al
    . Maternal placental infection with Plasmodium falciparum and malaria morbidity during the first 2 years of life. Am J Epidemiol 1997;146:826-31.
    Abstract/FREE Full Text
  3. ↵
    1. van Eijk AM,
    2. Ayisi JG,
    3. Ter Kuile FO,
    4. et al
    . Malaria and human immunodeficiency virus infection as risk factors for anemia in infants in Kisumu, western Kenya. Am J Trop Med Hyg 2002;67:44-53.
    Abstract
  4. ↵
    1. Bonner PC,
    2. Zhou Z,
    3. Mirel LB,
    4. et al
    . Placental malaria diminishes development of antibody responses to Plasmodium falciparum epitopes in infants residing in an area of western Kenya where P. falciparum is endemic. Clin Diagn Lab Immunol 2005;12:375-9.
    Medline
  5. ↵
    1. Mutabingwa TK,
    2. Bolla MC,
    3. Li JL,
    4. et al
    . Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS Med 2005;2:e407.
    CrossRefMedline
  6. ↵
    1. Slutsker L,
    2. Marston BJ
    . HIV and malaria: interactions and implications. Curr Opin Infect Dis 2007;20:3-10.
    MedlineWeb of Science
  7. ↵
    1. ter Kuile FO,
    2. Parise ME,
    3. Verhoeff FH,
    4. et al
    . The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-Saharan Africa. Am J Trop Med Hyg 2004;71:41-54.
    Abstract/FREE Full Text
  8. ↵
    1. Ned RM,
    2. Moore JM,
    3. Chaisavaneeyakorn S,
    4. Udhayakumar V
    . Modulation of immune responses during HIV-malaria co-infection in pregnancy. Trends Parasitol 2005;21:284-91.
    CrossRefMedlineWeb of Science
  9. ↵
    1. Ayisi JG,
    2. van Eijk AM,
    3. Newman RD,
    4. et al
    . Maternal malaria and perinatal HIV transmission, western Kenya. Emerg Infect Dis 2004;10:643-652.
    MedlineWeb of Science
    1. Brahmbhatt H,
    2. Kigozi G,
    3. Wabwire-Mangen F,
    4. et al
    . The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda. AIDS 2003;17:2539-41.
    CrossRefMedlineWeb of Science
  11. ↵
    1. Inion I,
    2. Mwanyumba F,
    3. Gaillard P,
    4. et al
    . Placental malaria and perinatal transmission of human immunodeficiency virus type 1. J Infect Dis 2003;188:1675-8.
    Abstract/FREE Full Text
  12. ↵
    1. Bloland PB,
    2. Wirima JJ,
    3. Steketee RW,
    4. Chilima B,
    5. Hightower A,
    6. Breman JG
    . Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection. AIDS 1995;9:721-6.
    MedlineWeb of Science
  13. ↵
    1. Ticconi C,
    2. Mapfumo M,
    3. Dorrucci M,
    4. et al
    . Effect of maternal HIV and malaria infection on pregnancy and perinatal outcome in Zimbabwe. J Acquir Immune Defic Syndr 2003;34:289-94.
    CrossRefMedlineWeb of Science
  14. ↵
    1. Verhoeff FH,
    2. Le Cessie S,
    3. Kalanda BF,
    4. Kazembe PN,
    5. Broadhead RL,
    6. Brabin BJ
    . Post-neonatal infant mortality in Malawi: the importance of maternal health. Ann Trop Paediatr 2004;24:161-9.
    CrossRefMedlineWeb of Science
  15. ↵
    1. van Eijk AM,
    2. Ayisi JG,
    3. Ter Kuile FO,
    4. et al
    . HIV, malaria, and infant anemia as risk factors for postneonatal infant mortality among HIV-seropositive women in Kisumu, Kenya. J Infect Dis 2007;196:30-7.
    Abstract/FREE Full Text
  16. ↵
    1. Ismaili J,
    2. van der Sande M,
    3. Holland MJ,
    4. et al
    . Plasmodium falciparum infection of the placenta affects newborn immune responses. Clin Exp Immunol 2003;133:414-21.
    CrossRefMedlineWeb of Science
  17. ↵
    1. De Milito A,
    2. Nilsson A,
    3. Titanji K,
    4. et al
    . Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 2004;103:2180-6.
    Abstract/FREE Full Text
  18. ↵
    1. de Moraes-Pinto MI,
    2. Almeida AC,
    3. Kenj G,
    4. et al
    . Placental transfer and maternally acquired neonatal IgG immunity in human immunodeficiency virus infection. J Infect Dis 1996;173:1077-84.
    MedlineWeb of Science
  19. ↵
    1. Scott S,
    2. Cumberland P,
    3. Shulman CE,
    4. et al
    . Neonatal measles immunity in rural Kenya: the influence of HIV and placental malaria infections on placental transfer of antibodies and levels of antibody in maternal and cord serum samples. J Infect Dis 2005;191:1854-60.
    Abstract/FREE Full Text
  20. ↵
    1. Ayisi JG,
    2. Branch OH,
    3. Rafi-Janajreh A,
    4. et al
    . Does infection with human immunodeficiency virus affect the antibody responses to Plasmodium falciparum antigenic determinants in asymptomatic pregnant women? J Infect 2003;46:164-72.
    CrossRefMedlineWeb of Science
  21. ↵
    1. Mount AM,
    2. Mwapasa V,
    3. Elliott SR,
    4. et al
    . Impairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by HIV infection. Lancet 2004;363:1860-7.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Ayisi JG,
    2. van Eijk AM,
    3. ter Kuile FO,
    4. et al
    . Risk factors for HIV infection among asymptomatic pregnant women attending an antenatal clinic in western Kenya. Int J STD AIDS 2000;11:393-401.
    Abstract/FREE Full Text
  23. ↵
    1. Hillier CJ,
    2. Ware LA,
    3. Barbosa A,
    4. et al
    . Process development and analysis of liver-stage antigen 1, a preerythrocyte-stage protein-based vaccine for Plasmodium falciparum. Infect Immun 2005;73:2109-15.
    Abstract/FREE Full Text
  24. ↵
    1. Ockenhouse CF,
    2. Barbosa A,
    3. Blackall DP,
    4. et al
    . Sialic acid-dependent binding of baculovirus-expressed recombinant antigens from Plasmodium falciparum EBA-175 to Glycophorin A. Mol Biochem Parasitol 2001;113:9-21.
    CrossRefMedlineWeb of Science
  25. ↵
    1. Dutta S,
    2. Lalitha PV,
    3. Ware LA,
    4. et al
    . Purification, characterization, and immunogenicity of the refolded ectodomain of the Plasmodium falciparum apical membrane antigen 1 expressed in Escherichia coli. Infect Immun 2002;70:3101-10.
    Abstract/FREE Full Text
  26. ↵
    1. Zhou Z,
    2. Xiao L,
    3. Branch OH,
    4. Kariuki S,
    5. Nahlen BL,
    6. Lal AA
    . Antibody responses to repetitive epitopes of the circumsporozoite protein, liver stage antigen-1, and merozoite surface protein-2 in infants residing in a Plasmodium falciparum-hyperendemic area of western Kenya. XIII. Asembo Bay Cohort Project. Am J Trop Med Hyg 2002;66:7-12.
    Abstract
  27. ↵
    1. Otieno RO,
    2. Ouma C,
    3. Ong'echa JM,
    4. et al
    . Increased severe anemia in HIV-1-exposed and HIV-1-positive infants and children during acute malaria. AIDS 2006;20:275-80.
    MedlineWeb of Science
  28. ↵
    1. Dent A,
    2. Malhotra I,
    3. Mungai P,
    4. et al
    . Prenatal malaria immune experience affects acquisition of Plasmodium falciparum merozoite surface protein-1 invasion inhibitory antibodies during infancy. J Immunol 2006;177:7139-45.
    Abstract/FREE Full Text
  29. ↵
    1. Brustoski K,
    2. Kramer M,
    3. Möller U,
    4. Kremsner PG,
    5. Luty AJ
    . Neonatal and maternal immunological responses to conserved epitopes within the DBL-γ3 chondroitin sulfate A-binding domain of Plasmodium falciparum erythrocyte membrane protein 1. Infect Immun 2005;73:7988-95.
    Abstract/FREE Full Text
    1. Desowitz RS
    . Prenatal immune priming in malaria: antigen-specific blastogenesis of cord blood lymphocytes from neonates born in a setting of holoendemic malaria. Ann Trop Med Parasitol 1988;82:121-5.
    MedlineWeb of Science
    1. King CL,
    2. Malhotra I,
    3. Wamachi A,
    4. et al
    . Acquired immune responses to Plasmodium falciparum merozoite surface protein-1 in the human fetus. J Immunol 2002;168:356-64.
    Abstract/FREE Full Text
  32. ↵
    1. Xi G,
    2. Leke RG,
    3. Thuita LW,
    4. et al
    . Congenital exposure to Plasmodium falciparum antigens: prevalence and antigenic specificity of in utero-produced antimalarial immunoglobulin M antibodies. Infect Immun 2003;71:1242-6.
    Abstract/FREE Full Text
  33. ↵
    1. Cumberland P,
    2. Shulman CE,
    3. Maple PA,
    4. et al
    . Maternal HIV infection and placental malaria reduce transplacental antibody transfer and tetanus antibody levels in newborns in Kenya. J Infect Dis 2007;196:550-7.
    Abstract/FREE Full Text
  34. ↵
    1. de Moraes-Pinto MI,
    2. Verhoeff F,
    3. Chimsuku L,
    4. et al
    . Placental antibody transfer: influence of maternal HIV infection and placental malaria. Arch Dis Child Fetal Neonatal Ed 1998;79:F202-5.
    Abstract/FREE Full Text
  35. ↵
    1. Schofield L,
    2. Uadia P
    . Lack of Ir gene control in the immune response to malaria. I. A thymus-independent antibody response to the repetitive surface protein of sporozoites. J Immunol 1990;144:2781-8.
    Abstract
  36. ↵
    1. Madhi SA,
    2. Kuwanda L,
    3. Cutland C,
    4. Holm A,
    5. Käyhty H,
    6. Klugman KP
    . Quantitative and qualitative antibody response to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected children. Pediatr Infect Dis J 2005;24:410-6.
    CrossRefMedlineWeb of Science
  37. ↵
    1. Thaithumyanon P,
    2. Punnahitananda S,
    3. Praisuwanna P,
    4. Thisyakorn U,
    5. Ruxrungtham K
    . Antibody response to hepatitis B immunization in infants born to HIV-infected mothers. J Med Assoc Thai 2002;85:277-82.
    Medline
  38. ↵
    1. Cot M,
    2. Le Hesran JY,
    3. Staalsoe T,
    4. Fievet N,
    5. Hviid L,
    6. Deloron P
    . Maternally transmitted antibodies to pregnancy-associated variant antigens on the surface of erythrocytes infected with Plasmodium falciparum: relation to child susceptibility to malaria. Am J Epidemiol 2003;157:203-9.
    Abstract/FREE Full Text
  39. ↵
    1. Riley EM,
    2. Wagner GE,
    3. Ofori MF,
    4. et al
    . Lack of association between maternal antibody and protection of African infants from malaria infection. Infect Immun 2000;68:5856-63.
    Abstract/FREE Full Text
  40. ↵
    1. Riley EM,
    2. Wagner GE,
    3. Akanmori BD,
    4. Koram KA
    . Do maternally acquired antibodies protect infants from malaria infection? Parasite Immunol 2001;23:51-9.
    CrossRefMedlineWeb of Science
  41. ↵
    1. Cavanagh DR,
    2. Dodoo D,
    3. Hviid L,
    4. et al
    . Antibodies to the N-terminal block 2 of Plasmodium falciparum merozoite surface protein 1 are associated with protection against clinical malaria. Infect Immun 2004;72:6492-502.
    Abstract/FREE Full Text
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  1. J Infect Dis. (2008) 198 (11): 1609-1619. doi: 10.1086/593066
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