Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA. 2011 305:6, 576-84.
To evaluate the relationship between maternal HIV status and the levels of antibodies (Ab) to vaccine-preventable diseases in uninfected infants at birth and following immunization; to compare levels of maternal antibodies between women who are HIV-infected and uninfected
Community health center in Western Cape Province, South Africa
Nested longitudinal cohort study
HIV uninfected and exposed, and HIV unexposed infants, and their mothers
Levels of specific Immunoglobulin G (IgG) to the following were measured in both mothers and infants at birth: Haemophilus influenza type b (Hib), pneumococcal capsular polysaccharide antigen, pertussis, tetanus toxoid, and hepatitis B surface antigen. The ratio of infant to maternal antibody levels at birth was used as a proxy for placental transfer. Antibody response following vaccination was measured in infants at 16 weeks.
Women already enrolled in a study on maternal HIV and tuberculosis (TB) infection and infant response to Bacillus Calmette-Guérin (BCG) vaccination for TB were included in the current study (2009-2010). Both HIV positive and negative women were included if they had delivered an infant within the last 24 hours, were over 18 years old, were healthy, and did not have TB. Infants were included if they weighed more than 2.5kg at birth, were delivered at least 36 weeks of gestation, were not acutely ill, were not a twin, and remained HIV-uninfected. Infants were tested for HIV with polymerase chain reaction (PCR) tests at 4 and 16 weeks. Infants who were HIV positive were excluded from analysis.
HIV positive mothers were given zidovudine (ZDV) starting at 28 weeks, and single-dose nevirapine (sd-NVP) at delivery. Their infants were also given NVP at delivery and one month of ZDV. All infants received immunizations according to national protocol including: oral polio, combination diphtheria, pertussis, tetanus and Hib (DPT-Hib) or with acellular pertussis and inactivated polio (DTaP-IPV/Hib); hepatitis B (hep B), pneumococcal 7-valent conjugate, rotavirus, and BCG only if HIV-uninfected. Blood samples for antibody testing were obtained from mother and infant within 24 hours of delivery, and from infants at 16 weeks. All HIV-infected women chose exclusive formula feeding; HIV-uninfected women were counseled to exclusively breastfeed. The mean CD4 count of HIV+ women at birth was 474 cells/µl (SD=252); seven women had CD4 counts of <200 cells/µl and were either on or referred for ART.
The final analysis was based on samples collected at birth for 100 women (46 HIV positive, 54 HIV negative) and infants, and from 93 infants at 16 weeks. At birth, HIV-exposed but uninfected infants had significantly lower antibody levels compared with unexposed infants to: Hib (0.37 vs. 1.02 mg/L); pertussis (16.1 vs. 36.1 FDA U/mL); pneumococcus (17.2 vs. 32.0 mg/L); tetanus (0.08 vs. 0.24 IU/mL) (all p<0.05). This corresponded to a lower proportion of HIV exposed infants vs. unexposed who had levels considered to be protective against: Hib (17% vs. 52%); pertussis (24% vs. 57%); tetanus (43% vs. 74%); hep B (21% vs. 54%) (all p≤0.01). In multiple regression analysis, HIV exposure was associated with reduced antibody titres to all antigens. Among mothers, HIV infected vs. uninfected women had lower specific Ab levels to Hib (0.67 vs. 1.34 mg/L) and pneumococcus (33.5 vs. 50.8 mg/L); there was no difference observed for pertussis and tetanus. HIV-infected women were less likely to have anti-Hib Ab levels considered protective (35% vs. 59%, p=0.02). The proportion of all women with protective antibody levels was low for pertussis (32%), tetanus (41%) and hep B (30%). In HIV-infected women, CD4 count (but not viral load) was positively correlated with levels of antibody to pertussis, pneumococcus and tetanus, but not Hib.
Among both HIV-infected and uninfected women and their infants, maternal and infant antibody responses were significantly correlated for Hib, pertussis, pneumococcus, and tetanus. Based on the ratio of infant-to-maternal antibody, HIV infected vs. uninfected women had significant reductions in placental transfer for Hib (23%), pertussis (40%), and tetanus (27%). At 16 weeks, HIV-exposed but uninfected infants mounted robust responses to vaccination; among those who received all three doses of DTP-Hib, HIV exposed vs. unexposed had significantly higher responses to pertussis, and similar responses to Hib and tetanus. Infants with the lowest levels of anti-Hib, pertussis, pneumococcal and tetanus Ab showed the greatest vaccine responses at 16 weeks; HIV exposure was associated with a greater level of change.
This study shows that HIV exposed uninfected infants compared to unexposed infants have lower specific antibody levels at birth, and a smaller proportion have Ab levels that are protective. The authors state that this is due to a combination of factors, including lower Ab levels in HIV-infected mothers and reduced transplacental transfer of Abs. The increased vaccine response in HIV-exposed infants can be explained by the lower levels of maternally derived Ab of birth. A significant proportion of HIV uninfected women also showed insufficient protection.
This was a high quality observational study with detailed analysis and presentation of results. Limitations included the small number of mother- infant pairs enrolled from a single setting. There is some uncertainty regarding what can be considered protective levels of antibodies, and the clinical relevance of single measurements. Because follow-up of infants was only 16 weeks, longer term vaccine responses and clinical outcomes were not assessed.
HIV-uninfected exposed infants and children have been shown to have increased rates of lower respiratory tract infections, meningitis, and mortality in the first year of life.(1,2) Two studies in Kenya showed that maternal HIV was associated with lower tetanus and measles-specific Ab in cord blood, and reduced placental Ab transfer.(3,4) Other studies have shown that maternal Ab can interfere with infants response to measles, tetanus, pertussis, and Hib vaccines.(5,6)
This interesting study indicates that the higher morbidity and mortality among African HIV-exposed but uninfected infants, particularly due to pneumonia.(1) may be due to the decreased levels of maternal and infant antibodies. The best strategy to reduce infections among infants early in life, however, is not clear. Immunizing women during pregnancy, although increasing infants maternally-derived Ab, may blunt subsequent infant response to vaccination.(7,8) Another alternative would be to immunize infants earlier; for example, neonatal pertussis vaccination is safe and results in early Ab response, although it may affect Hib and Hep B immunization response.(9) Further evaluation of maternal and neonatal vaccination strategies is still required.
- McNally LM, Jeena PM, Gajee K, Thula SA, Sturm AW, Cassol S, Tomkins AM, Coovadia HM, Goldblatt D. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet. 2007 Apr 28;369(9571):1440-51.
- Koyanagi A, Humphrey JH, Ntozini R, Nathoo K, Moulton LH, Iliff P, Mutasa K, Ruff A, Ward B; ZVITAMBO Study Group. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J. 2011 Jan;30(1):45-51
- Cumberland P, Shulman CE, Maple PA, Bulmer JN, Dorman EK, Kawuondo K, Marsh K, Cutts FT.
Maternal HIV infection and placental malaria reduce transplacental antibody transfer and tetanus antibody levels in newborns in Kenya. J Infect Dis. 2007 Aug 15;196(4):550-7. Epub 2007 Jun 29
- Scott S, Cumberland P, Shulman CE, Cousens S, Cohen BJ, Brown DW, Bulmer JN, Dorman EK, Kawuondo K, Marsh K, Cutts F. 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 Jun 1;191(11):1854-60. Epub 2005 Apr 20.
- Albrecht P, Ennis FA, Saltzman EJ, Krugman S. Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure. AIDS. 2006 Aug 1;20(12):1605-12
- Sarvas H, Kurikka S, Seppälä IJ, Mäkelä PH, Mäkelä O. Maternal antibodies partly inhibit an active antibody response to routine tetanus toxoid immunization in infants. J Infect Dis. 1992 May;165(5):977-9
- Hannah Blencowe, Joy Lawn,Jos Vandelaer, Martha Roper, and Simon Cousens. Tetanus toxoid immunization to reduce mortality from neonatal tetanus. Int J Epidemiol. 2010 April; 39(suppl_1): i102i109.
Published online 2010 March 23. doi: 10.1093/ije/dyq027.
- Knuf M, Schmitt HJ, Wolter J, Schuerman L, Jacquet JM, Kieninger D, Siegrist CA, Zepp F. Neonatal vaccination with an acellular pertussis vaccine accelerates the acquisition of pertussis antibodies in infants. J Pediatr. 2008;152(5):655-660, 660, e1.