A dose ranging study of 2 different formulations of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants.

BACKGROUND: Two new formulations of an investigational 15-valent pneumococcal conjugate vaccine (PCV15-A and PCV15-B) were developed using 2 different protein-polysaccharide conjugation processes and evaluated in separate phase I/II studies (NCT02037984 [V114-004] and NCT02531373 [V114-005]) to assess optimal concentrations of pneumococcal polysaccharide (PnPs) and Aluminum Phosphate Adjuvant. METHODS: Various lots of PCV15-A and PCV15-B containing different concentrations of PnPs and/or adjuvant were compared to PCV13 in young adults and infants. Adults received single dose and infants received 4 doses at 2, 4, 6, and 12-15 months of age. Adverse events (AEs) were collected after each dose. Serotype-specific immunoglobulin G (IgG) concentrations and opsonophagocytic activity (OPA) were measured prior and 30 days postvaccination in adults, at 1 month postdose 3 (PD3), pre-dose4, and postdose 4 (PD4) in infants. RESULTS: Safety profiles were comparable across vaccination groups. At PD3, serotype-specific IgG GMCs were generally lower for either PCV15 formulation than PCV13 for most shared serotypes. PCV15 consistently elicited higher antibody responses to the 2 serotypes unique to the vaccine (22F and 33F) and serotype 3 for which PCV13 was shown to be ineffective. Except for serotypes 6A and 6B, no dose-response effect was observed with increasing concentrations of PnPs and/or adjuvant. CONCLUSION: PCV15 is safe and induces IgG and OPA responses to all 15 serotypes in the vaccine. No significant differences in antibody responses were observed with increases in PnPs and/or Aluminum Phosphate Adjuvant.

Comparison of human immunodeficiency virus (HIV)-specific T-cell responses in HIV-1- and HIV-2-infected individuals in Senegal.

Human immunodeficiency virus type 2 (HIV-2) infection is typically less virulent than HIV-1 infection, which may permit the host to mount more effective, sustained T-cell immunity. We investigated antiviral gamma interferon-secreting T-cell responses by an ex vivo Elispot assay in 68 HIV-1- and 55 HIV-2-infected Senegalese patients to determine if differences relate to more efficient HIV-2 control. Homologous HIV-specific T cells were detected in similar frequencies (79% versus 76%, P = 0.7) and magnitude (3.12 versus 3.08 log(10) spot-forming cells/10(6) peripheral blood mononuclear cells) in HIV-1 and HIV-2 infection, respectively. Gag-specific responses predominated in both groups (>/=64%), and significantly higher Nef-specific responses occurred in HIV-1-infected (54%) than HIV-2-infected patients (22%) (P < 0.001). Heterologous responses were more frequent in HIV-1 than in HIV-2 infection (46% versus 27%, P = 0.04), but the mean magnitude was similar. Total frequencies of HIV-specific responses in both groups did not correlate with plasma viral load and CD4(+) T-cell count in multivariate regression analyses. However, the magnitude of HIV-2 Gag-specific responses was significantly associated with lower plasma viremia in HIV-1-infected patients (P = 0.04). CD4(+) T-helper responses, primarily recognizing HIV-2 Gag, were detected in 48% of HIV-2-infected compared to only 8% of HIV-1-infected patients. These findings indicate that improved control of HIV-2 infection may relate to the contribution of T-helper cell responses. By contrast, the superior control of HIV-1 replication associated with HIV-2 Gag responses suggests that these may represent cross-reactive, higher-avidity T cells targeting epitopes within Gag regions of functional importance in HIV replication.

Ontogeny and specificities of mucosal and blood human immunodeficiency virus type 1-specific CD8(+) cytotoxic T lymphocytes.

Induction of adaptive immunity to human immunodeficiency virus type 1 (HIV-1) at the mucosal site of transmission is poorly understood but crucial in devising strategies to control and prevent infection. To gain further understanding of HIV-1-specific T-cell mucosal immunity, we established HIV-1-specific CD8(+) cytotoxic T-lymphocyte (CTL) cell lines and clones from the blood, cervix, rectum, and semen of 12 HIV-1-infected individuals and compared their specificities, cytolytic function, and T-cell receptor (TCR) clonotypes. Blood and mucosal CD8(+) CTL had common HIV-1 epitope specificities and major histocompatibility complex restriction patterns. Moreover, both systemic and mucosal CTL lysed targets with similar efficiency, primarily through the perforin-dependent pathway in in vitro studies. Sequence analysis of the TCRbeta VDJ region revealed in some cases identical HIV-1-specific CTL clones in different compartments in the same HIV-1-infected individual. These results clearly establish that a subset of blood and mucosal HIV-1-specific CTL can have a common origin and can traffic between anatomically distinct compartments. Thus, these effectors can provide immune surveillance at the mucosa, where rapid responses are needed to contain HIV-1 infection.

Human immunodeficiency virus-specific and CD3-redirected cytotoxic T lymphocyte activity in the human female reproductive tract: lack of correlation between mucosa and peripheral blood.

CD8(+) T cell phenotype and function were assessed in the female reproductive tracts (FRTs) of 3 human immunodeficiency virus (HIV)-positive patients who had undergone hysterectomy. FRT cytotoxic T lymphocyte (CTL) lytic activity from 1 patient (patient 872) was detected by using CD3-dependent redirected-lysis assay and HIV-specific assay, concomitant with the presence of CD8(+) cells. In contrast, samples from the 2 other HIV-positive patients (patients 1356 and 1364), who also were asymptomatic for HIV-associated illnesses, demonstrated no CTL activity in any solid tissue tested by either assay, despite activity by autologous peripheral blood mononuclear cells (PBMC). This absence of CTL activity was correlated with a relative absence of CD8(+) cells in the FRT, whereas CD8(+) cells were present in PBMC. Thus, CTL activity in PBMC may fail to correlate with mucosal activity. The finding of CTL activity in the FRT of patient 872 represents the first description of CTL in upper and lower FRT tissues of an HIV-positive woman.

Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection.

T-cell responses were evaluated prospectively in 41 patients with acute human immunodeficiency virus type 1 (HIV-1) infection (30 untreated and 11 receiving zidovudine, lamivudine, and indinavir) and in 38 uninfected adults. By 6-12 months, treated patients had significantly greater median Candida and tetanus lymphoproliferative responses (stimulation index [SI], 76 and 55, respectively) than did untreated patients (SI, 7 and 6, P=.02 and.001, respectively), and the responses of treated patients surpassed those of uninfected adults (SI, 19 and 32, P= .002 and .101, respectively). Unlike the patients in the untreated group, the patients in the treated group mounted a 6-fold increased HIV-1 p24 response (SI increase, 1.0 to 5.7, P= .01) within 3 months. HIV-1-specific cytotoxicity remained detectable in most treated patients. Thus, combination therapy administered within 3-4 months of infection was associated with improved T-cell memory responses that were distinct from those of untreated patients. The amplified HIV-1-specific T-cell responses may help maintain cytotoxic activities.

Early and persistent human immunodeficiency virus type 1 (HIV-1)-specific T helper dysfunction in blood and lymph nodes following acute HIV-1 infection.

Without potent antiretroviral therapy, most human immunodeficiency virus type 1 (HIV-1)-infected persons experience a progressive decline in CD4+ T cells and impairment in T helper function. It is unclear how soon after infection T cell dysfunction occurs. T helper responses were examined in blood and lymphoid tissue of 39 untreated patients with acute HIV-1 infection. Within the first 3 months, lymphoproliferative responses to mitogen, recall antigens, and HIV-1 antigens were impaired. After 6-9 months, responses to phytohemagglutinin and recall antigens improved. However, HIV-1-specific lymphoproliferation remained largely undetectable throughout 2 years of infection, and results were similar upon evaluation of lymphoid cells. Rare patients with HIV-1-specific responses had significantly lower plasma HIV-1 RNA levels than did nonresponders. These results indicate that T helper dysfunction occurs early after HIV-1 acquisition and that untreated individuals rarely recover HIV-specific helper responses; these findings lend support for early therapeutic intervention to prevent the destruction and further impairment of the T helper cells.

Protection against human immunodeficiency virus type 1 infection in persons with repeated exposure: evidence for T cell immunity in the absence of inherited CCR5 coreceptor defects.

It has been hypothesized that protection against human immunodeficiency virus (HIV)-1 infection may result from either acquired host immunity, inheritance of a dysfunctional CCR5 HIV-1 coreceptor, or a low or attenuated virus inoculum. Thirty-seven HIV-1-uninfected persons engaging in repeated high-risk sexual activity with an HIV-1-infected partner were prospectively studied to determine the contribution of these factors in protecting against HIV-1 transmission. More than one-third (13/36) demonstrated HIV-1-specific cytotoxicity, and this activity significantly correlated with the wild type CCR5 genotype (P=.03). Only 1 subject (3%) demonstrated the homozygous CCR5 32-bp deletion (Delta32/Delta32). Median plasma HIV-1 RNA levels from 18 HIV-1-infected sex partners were not statistically different from those of matched infected control patients. These results indicate that inheritance of the Delta32 CCR5 mutation does not account for the majority of persistently HIV-1-resistant cases, and the presence of cellular immunity in these persons suggests either undetected infection or protective immunity.

Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection.

BACKGROUND: Early in human immunodeficiency virus type 1 (HIV-1) infection there is a decline in viral replication that has been attributed to host immunity, but the components of this response, particularly the ability of cytotoxic T lymphocytes to control viral burden and influence the outcome of disease, are poorly understood. METHODS: We prospectively studied 33 patients with primary HIV-1 infection for HIV-specific activated cytotoxic T lymphocytes and memory cytotoxic T lymphocytes and compared these lymphocyte responses with changes in viral load and clinical status over the subsequent 18 to 24 months. RESULTS: Soon after infection, activated HIV-specific cytotoxic T lymphocytes, mediated primarily by CD8+ cells, were detected in 17 of 23 patients (74 percent). Memory cytotoxic T lymphocytes were found in 6 of 6 patients tested (100 percent) during the first three months of infection and in 17 of 21 patients (81 percent) tested during the first six months. The frequencies of memory cytotoxic T lymphocytes varied markedly over time, but overall they declined over the first 6 to 8 months and then stabilized over the next 12 to 18 months. The patients with higher frequencies of Env-specific memory cytotoxic T lymphocytes had a median level of plasma HIV-1 RNA about one third that of the patients with lower frequencies, (median number of RNA copies per milliliter, 22,000 vs. 62,000; P=0.006). Patients with low frequencies of Env-specific memory cytotoxic T lymphocytes (or none) in early infection had a more rapid decline to less than 300 CD4+ cells per cubic millimeter (P = 0.05). CONCLUSIONS: In early HIV-1 infection, the induction of memory cytotoxic T lymphocytes, particularly those specific for Env, helps control viral replication and is associated with slower declines in CD4+ cell counts. Host cytolytic effector responses appear to delay the progression of HIV-1 disease.

Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses.

The rate of progression to AIDS in human immunodeficiency virus type 1 (HIV-1)-infected individuals is determined by a complex series of interactions between the host and virus. Here we evaluate virologic properties and host responses in two men near-simultaneously infected with HIV-1 from the same sexual partner--one individual progressed to AIDS in less than 2 years, and the other remains asymptomatic 3 years postinfection. Distinct neutralizing antibody and cellular immune responses were evident, with the slower progressor exhibiting generally stronger and broader responses, except for cytotoxic T-lymphocyte responses early in infection. Virtually identical, homogeneous virus populations were found in both patients in the first sample obtained; however, a second unrelated HIV-1 virus population was also found in the fast progressor. Whether the second population emanated from an additional source of infection or the two were transmitted from the original source could not be determined. The virus population in the slower progressor turned over and diversified rapidly, whereas both virus populations in the rapid progressor evolved at a much slower rate. In addition, the character of mutational changes underlying these diversities appeared to be distinct, with a bias for diversifying selection developing in the slower progressor and a reciprocal bias towards purifying selection maintained in both populations in the fast progressor. Thus, the rapid evolution that is a hallmark of HIV replication may be a reflection of strong host resistance against emerging virus variants and a longer period of asymptomatic infection. Furthermore, rapid progression was not linked to a collapse of any appreciable immune response following attainment of some threshold of antigenic diversity but rather to a failure to drive this diversification and a condition of relatively unimpeded expansion of variants with optimized replicative capacity within the host.

HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women.

Although T lymphocytes are present in the genital mucosa, their function in sexually transmitted diseases is unproven. To determine if cervical T cells mediate HIV-specific cytolysis, mononuclear cells in cytobrush specimens from HIV-1-infected women were stimulated in vitro with antigen. Resultant cell lines lysed autologous targets expressing HIV-1 proteins in 12/19 (63%) subjects, and these responses were detected intermittently on repeated visits. All 8 subjects with blood CD4+ counts > or =500 cells/microl had HIV-1-specific cervical CTL, whereas only 4/11 with counts <500 cells/microl had detectable responses (P = 0.008). Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1. Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids. Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood. These studies provide the first definitive evidence for an MHC-restricted effector function in human cervical lymphocytes.

Elevated levels of tumor necrosis factor-alpha in Zairian neonate plasmas: implications for perinatal infection with the human immunodeficiency virus.

Plasma levels of tumor necrosis factor-alpha (TNF alpha) and the ability of plasmas to induce HIV expression in chronically infected cell lines were measured in samples from adults, cord blood, and neonates from Zaire and North America. Plasma levels of TNF alpha were higher in Zairian neonates born to HIV-negative and -positive mothers than in uninfected Zairian adults (612 vs. 128 vs. 8 pg/mL, P < .001); this dichotomy persisted until children were 9 months old. Plasmas from neonates of HIV-negative Zairian mothers also stimulated higher levels of reverse transcriptase from HIV-infected cell lines than did plasma from HIV-negative Zairian adults (1339 vs. 110 cpm, P < .001). Similar patterns were noted in plasmas from HIV-negative North American adults and neonates; however, TNF alpha levels were markedly lower, and smaller differences were noted among North American adults and neonates than those in the Zairian cohort. Markedly elevated plasma TNF alpha levels in Zairian neonates and infants may play a role in the pathogenesis and progression of HIV disease in this patient population.