To the Editor—It is well known that individuals living with perinatally acquired human immunodeficiency virus (HIV) have substantial dyscrasias inside the B-cell compartment, affecting their immune response to vaccines [1–3]. However, it is not known the rate at which these individuals lose their cellular and serological immunity to immunizations.
More than 20 years ago, before the wide availability of combined antiretroviral therapy (ART), we documented that 54% of children attending our clinic and living with perinatally acquired HIV who received hepatitis B virus (HBV) vaccination (HBVv; Engerix-B, 3 doses) failed to mount detectable antibody responses to vaccination. We subsequently showed that rates of seroconversion could be increased to 65% by a second 3-dose series of HBVv [4].
We evaluated 10 children and adolescents (8 of the 10 participated in previous above-mentioned studies) who seroconverted after the second series of HBVv and who were on ART at the time of the second series of HBVv for persistence of plasma antibodies and T-cell and B-cell responses to HBVv at 4, 6, and 10 years from last HBVv (second-dose series). Twenty-two HIV-uninfected adults (≥18 years of age) served as controls for HBVv immunity. It has been shown that vaccine memory and long-term protection after completing HBVv lasts for at least 20–30 years [5]. Plasma immunoglobulin G to hepatitis B surface antigen was determined by enzyme-linked immunosorbent assay (My BioSource) and B- and T-cell memory to HBV by enzyme-linked immunosorbent spot assay [6, 7]. Clinical laboratory results including absolute CD4 cell count, percentage, and viral load were extracted from electronic medical records and matched the blood samples collected for tests described previously. Findings for the HIV-positive group are presented as a ratio to the matched outcome for the HIV-negative group. Categorical and continuous variables are compared by Fisher test and Wilcoxon rank-sum test.
At initiation of ART, the median age of participants was 4.5 (interquartile range [IQR], 3.2–12.4) years, median CD4% was 23.4 (IQR, 18–31), and plasma median HIV RNA was 4.3 (IQR, 3.1–5.2) log10 copies/mL. Median CD4% and plasma HIV RNA log10 copies/mL at 4, 6, and 10 years from last HBVv were, respectively, 28 and 3.2; 27.9 and 2.9; and 29.5 and 2.4. In Figure 1 and Table 1, HBV plasma antibody, T-memory, and B-memory responses for HIV-negative controls are normalized to the dashed line at 1. All HIV-positive patients had detectable immune responses to HBVv. At 4 years after HBVv, the patients living with HIV had more robust B-memory responses than the HIV-negative group, and this persisted at 6 years but not 10 years after vaccination. At all intervals, HBV-specific T-memory and plasma antibodies were demonstrated, but at levels lower than those in adult controls.
Figure 1.
Comparison of hepatitis B virus (HBV) immunoglobulin G surface antibody and B- and T-cell memory immune responses to HBV between individuals living with perinatally acquired human immunodeficiency virus (HIV) and HIV-negative individuals. Abbreviations: HBVv, hepatitis B virus vaccination; HIV, human immunodeficiency virus.
Table 1.
Cellular and Serologic Responses to Hepatitis B Virus (HBV) Vaccine Between Individuals Living with Perinatally Acquired Human Immunodeficiency Virus (HIV) and HIV-Negative Individuals
| Parameter | At ART Initiation | 4 y | 6 y | 10 y | HIV-Negative | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Median | (IQR) | Median | (IQR) | Median | (IQR) | Median | (IQR) | Median | (IQR) | |
| Total IgG ASC/106 PBMCs | … | … | 48 407.6 | (39 171–57 643) | 48 089.2 | (35 350.3–62 738.8) | 12 579.6 | (10 828–15 605.1) | 32 515.9 | (22 200–55 070.1) |
| Specific HBV IgG ASC/106 PBMCs | … | … | 1950 | (1340–2330) | 693.3 | (466.7–1166.7) | 118.3 | (46.7–306) | 311.1 | (205–548.5) |
| Anti IgG HBs | … | … | 10.9 | (3.4–22.1) | 14.6 | (5.2–17.8) | 2.2 | (0.2–9.1) | 32.5 | (30.3–35.7) |
| IFN-γ SFC/106 PBMCs phytohemagglutinin | … | … | 12 620.7 | (6327–19 498) | 8245.3 | (4832.8–10 656) | 6993 | (1998–8325) | 26 818.5 | (25 974–28 302.7) |
| IFN-γ SFC/106 PBMCs HBV vaccine | … | … | 174.9 | (133.6–188.1) | 77.5 | (46.6–132) | 54.4 | (26.4–82.5) | 163.3 | (127–174.9) |
| HIV RNA, log10 copies/mL | 4.3 | (3.1–5.2) | 4.29 | (3.1–5.2) | 3.2 | (2.6–4.1) | 2.9 | (2.6–3.7) | 2.4 | (1.7–3.4) |
| CD4 count, cells/mL | 429 | (286.5–584.2) | 507 | (370–904) | 884 | (326–1269) | 838.5 | (423–1107) | 736 | (420–858) |
The column headings 4 y, 6 y, and 10 y represent the time after HBV vaccination.
Abbreviations: ART, antiretroviral therapy; ASC, antibody secreting cells; HBs, hepatitis B antibody; HBV, hepatitis B virus; HIV, human immunodeficiency virus; IFN-γ, interferon gamma; IgG, immunoglobulin G; IQR, interquartile range; PBMCs, peripheral blood mononuclear cells.
In this longitudinal study we show that serological immunity to hepatitis B among perinatally HIV-infected individuals did not persist at 10 years following a second HBVv booster immunization and that T- and B-cell memory to HBV declined markedly by year 10. It is notable that these patients had good virological control of HIV and immunological reconstitution of CD4 cells by ART. The discrepancy in levels of B-cell memory and plasma anti-HBV antibody is unexplained, and the association of this finding with the demonstration of an accumulation of exhausted B cells in our population requires further explanation [3]. Our study was limited by a sample size of 10 individuals and all outcomes were descriptive; therefore, results should be interpreted with caution. Second, we were not able to assess the compartment of the long-lived plasma cells and determine if the observed decline on HBVv antibodies was due to loss of these cells. Third, we do not have data regarding the time of HBVv for controls, and this can limit the interpretation for persistent HBVv memory. In conclusion, the long-term immune response to HBVv in perinatally infected individuals living with HIV appears to be compromised and our data suggest that it does not last more than 4 years; further studies with a larger sample size are needed to confirm these findings. Targeted strategies are required for more successful immunization where immunity does not persist despite booster vaccination and effective ART.
Contributor Information
German A Contreras, Division of Infectious Diseases, Department of Pediatrics, McGovern Medical School at UTHealth Houston, and Children’s Memorial Hermann Hospital, Houston, Texas, USA; Division of Infectious Diseases, Department of Internal Medicine, University of Texas UTHealth, Houston, Texas, USA.
Gilhen Rodriguez, Division of Infectious Diseases, Department of Pediatrics, McGovern Medical School at UTHealth Houston, and Children’s Memorial Hermann Hospital, Houston, Texas, USA.
Gabriela Del Bianco, Division of Infectious Diseases, Department of Pediatrics, McGovern Medical School at UTHealth Houston, and Children’s Memorial Hermann Hospital, Houston, Texas, USA.
Norma Pérez, Division of Infectious Diseases, Department of Pediatrics, McGovern Medical School at UTHealth Houston, and Children’s Memorial Hermann Hospital, Houston, Texas, USA.
James R Murphy, Division of Infectious Diseases, Department of Pediatrics, McGovern Medical School at UTHealth Houston, and Children’s Memorial Hermann Hospital, Houston, Texas, USA.
Gloria P Heresi, Division of Infectious Diseases, Department of Pediatrics, McGovern Medical School at UTHealth Houston, and Children’s Memorial Hermann Hospital, Houston, Texas, USA.
Notes
Author contributions. G. A. C. and J. R. M. contributed to study design, laboratory test development, data analysis, manuscript preparation, and manuscript review. G. R., G. D. B., N. P., and G. P. H. contributed to study design and manuscript review.
Patient consent. The institutional review board of McGovern Medical School UTHealth Houston approved the study (HSC-MS-03-296), and the patient’s written consent was obtained before enrollment in the study.
Financial support. This work was supported by the State of Texas Pediatric HIV Initiative.
Potential conflicts of interest. All authors: No reported conflicts of interest.
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