Robin P. Garner

Safety and immunogenicity of an HIV subtype B and E prime-boost vaccine combination in HIV-negative Thai adults

ALVAC-HIV (vCP1521) and AIDSVAX B/E were evaluated in a phase 1/2 trial of human immunodeficiency virus (HIV)-negative Thai adults. Of 133 volunteers enrolled, 122 completed the trial. There were no serious vaccine-related adverse events, nor were there intercurrent HIV infections. Lymphoproliferative responses to glycoprotein 120 E were induced in 63% of the volunteers, and HIV-specific CD8 cytotoxic T lymphocyte responses were induced in 24%. Antibody responses increased in frequency and magnitude in association with the dose level of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain were induced in 100% and 98%, respectively, of the volunteers receiving 600 microg of AIDSVAX B/E, and such antibodies to E strains were induced in 96% and 71%, respectively, of these volunteers. This vaccine combination was well tolerated and was immunogenic, meeting milestones for advancement to phase 3 evaluation.

Safety and Immunogenicity of Combinations of Recombinant Subtype E and B Human Immunodeficiency Virus Type 1 Envelope Glycoprotein 120 Vaccines in Healthy Thai Adults

Safety and immunogenicity of 2 recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein (gp) 120 vaccines derived from SF2 (subtype B) and CM235 (CRF01_AE, Thai E) were evaluated in 370 Thai adults at low risk of HIV infection. Various doses of CM235 (25, 50, or 100 microg) and SF2 (0, 25, or 50 microg) gp120 were used. Eighty volunteers received placebo. There were no serious adverse events related to vaccination. Binding antibody developed in all vaccine recipients. There was no dose response to CM235 gp120, but a dose response to gp120 SF2 was present. Neutralizing antibodies to subtype E HIV-1 NPO3 and subtype B HIV-1 SF2 developed in 84% and 82% of vaccine recipients, respectively. Lymphoproliferative responses were detected in >95% of vaccine recipients. There was no evidence of antigenic interference in HIV-specific humoral or cellular responses. The gp120 Thai E and SF2 vaccines were safe and immunogenic in combination and could be advanced into phase 3 testing.

Efficacy Testing of Recombinant Human Immunodeficiency Virus (HIV) gp160 as a Therapeutic Vaccine in Early-Stage HIV-1-Infected Volunteers

A phase II efficacy trial was conducted with recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp160 (rgp160) in 608 HIV-infected, asymptomatic volunteers with CD4+ cell counts >400 cells/mm3. During a 5-year study, volunteers received a 6-shot primary series of immunizations with either rgp160 or placebo over 6 months, followed by booster immunizations every 2 months. Repeated vaccination with rgp160 was safe and persistently immunogenic. Adequate follow-up and acquisition of endpoints allowed for definitive interpretation of the trial results. There was no evidence that rgp160 has efficacy as a therapeutic vaccine in early-stage HIV infection, as measured at primary endpoints (50% decline in CD4+ cell count or disease progression to Walter Reed stage 4, 5, or 6) or secondary endpoints. A transient improvement was seen in the secondary CD4 endpoint for the vaccination compared with the placebo arm, but this did not translate into improved clinical outcome.

Repeated Immunization with Recombinant gp160 Human Immunodeficiency Virus (HIV) Envelope Protein in Early HIV-1 Infection: Evaluation of the T Cell Proliferative Response

This longitudinal study was designed to evaluate cellular immunity in early-stage, asymptomatic human immunodeficiency virus (HIV)-1-infected persons (CD4 cell count,>400/mm3; median, 625/mm3) who were immunized with either recombinant (r) gp160 or placebo every 2 months for 5 years. Proliferative responses were assessed against rgp160, rp24, and a panel of recall antigens and mitogens. Despite good reactivity to recall antigens, at baseline approximately 33% had proliferative responses to gp160, and approximately 42% showed p24 gag responses. There was no statistical difference between vaccine and placebo groups for antigens or mitogens. After 1 year, approximately 73% of the subjects in the vaccine arm had new or boosted responses to gp160, versus approximately 18% in the placebo arm. Statistical significance was maintained throughout the study. Recurrent vaccination with recombinant gp160 was proven to be persistently immunogenic, increasing significantly the ability of HIV-1-infected persons to mount new proliferative responses to the vaccine.

Major histocompatibility complex genotype is associated with disease progression and virus load levels in a cohort of human immunodeficiency virus type 1-infected caucasians and African Americans

To assess the influence of HLA on AIDS-free survival, human immunodeficiency virus load, and CD4 cell counts, 91 Caucasian and 48 African-American seroprevalent men were typed for HLA classes I and II and TAP alleles. HLA associations with these markers were assessed by assigning sum integer scores based on 7 class I allele-TAP variants (+1) and 13 class I-class II-TAP combinations (-1) with different AIDS-free survival times found in a prior study. Subjects in both racial groups and combined with positive sum scores were less likely to have CD4 cell decline (P=.0004), to have increased virus burden (P=.014), and to develop AIDS (P=.034) in the follow-up period than were Caucasians and African Americans with scores of 0 or -1. These results confirm the reported associations of specific major histocompatibility complex genes with AIDS-free survival time in Caucasians and specifically extend them to African Americans and to two established markers of disease progression.

HIV-1 seroconversion in United States Army active duty personnel, 1985-1999.

Objective To monitor HIV-1 infection trends among United States Army personnel, a predominantly young population group, tested between 1985 and 1999 for HIV-1 infection. Design Demographic correlates of HIV-1 infection were assessed in the cohort via epidemiologic analysis. Methods Annual seroconversion incidence rates were calculated per 1000 person-years (PY) of follow-up. Poisson regression was used to assess demographic correlates of HIV-1 seroconversion risk. Results There were 1275 seroconverters among 2 004 903 active duty Army personnel accounting for 7 700 231 PY of follow-up. The HIV-1 incidence rate (IR) was 0.17/1000 PY [95% confidence interval (CI), 0.16–0.17]. The highest IR was observed in the first year of testing (IR, 0.43/1000 PY; 95% CI, 0.33–0.52). The IR for male and female soldiers was 0.18/1000 PY and 0.08/1000 PY, respectively. HIV-1 incidence declined with age. Significant risk of HIV-1 seroconversion was associated with age [> 30 years old relative risk (RR), 1.51], race (Black RR, 4.61; Hispanic RR, 2.76), gender (male RR, 3.12), marital status (unmarried RR, 2.01) and rank (enlisted RR, 2.50). Conclusions HIV-1 seroconversions in the US Army have been low and stable since the early 1990s. Continued HIV-1 incidence surveillance in the US Army provides information on the status of the epidemic in the Army, as well as important corroborative data on HIV-1 infections throughout the US.

A Comparative Study of the Impact of HIV Infection on Natural Killer Cell Number and Function in Thais and North Americans

Innate immunity may play a role in preventing HIV infection and progression to AIDS. Most studies of natural killer (NK) cell function have been conducted in populations with different HLA allele frequencies and HIV subtypes than those found in Southeast Asia. NK cell number and function, defined as CD3- cells expressing CD16+/CD56+ and the ability to lyse K562 cells, were enumerated in 42 HIV-seronegative Thais and 20 HIV-seronegative North Americans. The number and percentage of NK cells were similar for both groups, but cytotoxicity function expressed as lytic units (LU20) of NK cells was significantly greater in the Thai subjects compared with the North American subjects (p = 0.004). Comparisons were also conducted between the HIV-seronegative groups and HIV-infected subjects from both Thailand and North America. NK cell number and function were not significantly different between the Thai HIV-seronegative and -seropositive groups. However, the comparison between the North American HIV-seronegative and -seropositive subjects demonstrated profound impairment of NK cell number, percentage, and function (p < 0.001). Matching the Thai and North American HIV-infected subjects on CD4+ cell count revealed higher NK number and function in the Thai subjects (p < 0.001). The study indicates that NK function in both HIV-seronegative and -seropositive Thais is elevated relative to similar groups in North America.

CD38 expression on cryopreserved CD8+ T cells predicts HIV disease progression.

Previous studies have revealed that the expression of CD38 on CD8+ T cells is a strong predictor of disease progression in human immunodeficiency virus (HIV)-infected individuals. Those studies were performed using fresh patient samples over an extended trial period. After demonstrating the validity of assay results on cryopreserved cells, we performed a retrospective study using frozen cell samples to determine the predictive value of CD38 expression in patients with CD4 counts above 400 cells/microl. The CD38 expression as measured by antibody binding capacity and the CD38 median channel were shown to be associated with time to new opportunistic infection or death (both P < 0.001). These results suggest that CD38 expression on CD8+ T cells, whether fresh or frozen, provides a useful predictor of HIV disease progression.

HIV type 1 subtype E-infected patients with broadened, dual (B/E) V3 loop serology have increased cross-neutralizing antibodies

The two prevalent subtypes of HIV-1 circulating in Thailand are subtypes E and B. While the most prevalent subtype continues to be E using molecular typing assays, immunologically, a subset of subtype E-infected patients (3.4% in 1997) have binding antibodies to both the E and B V3 loops in a peptide ELISA. To assess the potential function of this dual (B/E) V3 reactivity, plasmas from patients with genetically defined HIV-1 subtype E infection and either E or B/E V3 serotypes were compared for magnitude and breadth of neutralization of seven primary and laboratory-adapted subtype B and E viruses. Dually reactive (B/E) plasmas showed significantly increased cross-neutralizing activity against subtype B viruses (p < 0.001), and increased neutralization of the panel of viruses overall (p < 0.02), as compared to monoreactive E serotype plasmas. While the total envelope binding antibody titers to both subtype B and E envelopes did not differ significantly between the E and B/E plasmas, 67% of B/E plasmas neutralized >50% of the viruses in the panel, and only 14% of E plasmas showed this broadened neutralizing activity. These data suggest that dual (B/E) V3 loop reactivity may be a marker of broader immune recognition of HIV envelope epitopes in subtype E-infected patients. V3 loop antibody, perhaps in conjunction with antibodies to additional epitopes, may play a role in neutralization of virus isolates from Thailand.

Antibody-dependent cellular cytotoxicity in HIV type 1-infected patients receiving VaxSyn, a recombinant gp160 envelope vaccine.

Antibody-dependent cellular cytotoxicity (ADCC) activity was measured in 60 human immunodeficiency virus (HIV-1)-infected patients receiving a recombinant gp160 (rgp160) envelope protein of HIV-1(NL4-3) in alum and 64 receiving placebo over a 5-year study period. There was no difference in the percentage of ADCC responders when comparing rgp160-immunized patients (mean, 78.4%) with those receiving placebo alone (mean, 81.5%) at any time point examined. Patients were further divided into progression groups regardless of their vaccine status. ADCC activity was somewhat higher in rapid than in slow-progressing groups, although the number that had detectable ADCC activity was equivalent in each group. ADCC activity of sera from rapid- and slow-progressing groups against primary or laboratory isolate envelopes was similar. This study showed that transcription with rgp160 did not appear to enhance HIV-specific ADCC activity. ADCC activity did not appear to correlate with protection against AIDS in this cohort of HIV-1-infected people.