MN and IIIB recombinant glycoprotein 120 vaccine-induced binding antibodies to native envelope glycoprotein of human immunodeficiency virus type 1 primary isolates. National Institute of Allergy and Infectious Disease Aids Vaccine Evaluation Group.

The ability of antibody induced by MN and IIIB recombinant gp120 (rgp120) human immunodeficiency virus type 1 (HIV-1) vaccines to bind to oligomeric native HIV-1 envelope glycoproteins of primary isolates of HIV-1 was measured by flow cytometric indirect immunofluorescence assay (FIFA) in 25 uninfected, healthy adults. After three immunizations, MN rgp120 HIV-1 vaccine given alone and coadministered with IIIB rgp120 HIV-1 vaccine elicited antibody that bound to cells infected with each of a panel of six subtype B strains of HIV-1. Lower levels of vaccine-induced binding antibody were detected against envelope subtype A, D, and (EA) strains of HIV-1 than against subtype B strains. Priming immunization with IIIB rgp120 HIV-1 vaccine alone induced low levels of antibody capable of binding to envelope glycoprotein of primary isolate strains of HIV-1, and booster immunizations with MN rgp120 HIV-1 vaccine resulted in much higher antibody levels. We conclude that MN rgp120 HIV-1 vaccine was an effective inducer of antibody to native envelope glycoproteins of antigenically diverse primary isolates of HIV-1.     

Live attenuated varicella vaccine: protection in healthy adults compared with leukemic children. National Institute of Allergy and Infectious Diseases Varicella Vaccine Collaborative Study Group

Protection against varicella infection was assessed in leukemic children and healthy young adults who were immunized with live attenuated varicella vaccine. Attack rates of breakthrough infection following household exposure to varicella in 102 children and 26 adults were similar whether one or two doses of vaccine had been given. The mild breakthrough illness was also similar after one or more doses. Specific antibody titers were similar 1 year after immunization whether individuals had received one or two doses. Humoral and cell-mediated immunity to varicella-zoster virus (VZV) was lower in these vaccinees than in persons who had experienced natural varicella infection. Protection after natural infection in adult family members exposed to varicella was superior to that in vaccinees; none developed varicella infection. These observations suggest that immunization induces less protection than does natural disease in leukemic children and young adults. This may be partly due to the nature of the vaccine virus, but because responses of adults were similar to those of leukemic children, it suggests also that both of these groups have impaired immune responses to VZV. Boosting of humoral immunity after exposure to VZV was common and was observed in healthy adults with past natural infection and in vaccinated adults and leukemic children.     

Characterization of serum antibody responses to recombinant HIV-1 gp160 vaccine by enzyme immunoassay. NIAID AIDS Vaccine Clinical Trials Network.

An enzyme immunoassay (EIA) was developed to measure serum antibody responses of healthy adult volunteers vaccinated with 40 or 80 micrograms of human immunodeficiency virus type 1 (HIV-1) recombinant gp160 (rgp160) vaccine at 0, 1, 6, and 18 months. This assay, which used purified rgp160 as antigen, was compared with the Biotech/Du Pont HIV-1 Western blot and the Abbott HIV-1 EIA. Of 33 volunteers who received three doses of rgp160 vaccine, seroresponses were detected in 91% by rgp160 EIA, 97% by Western blot, and 30% by HIV-1 EIA. The level of IgG rgp160 EIA antibody (mainly IgG1) peaked after the third immunization; 64% of 33 vaccinees still had detectable antibody by 12 months. The fourth immunization induced anamnestic IgG EIA antibody in 23 of 24 vaccinees, with titers ranging from 1:200 to 1:25,600. Neutralizing antibody was not detected in postvaccination sera by microtiter syncytium formation inhibition assay. Additional testing of sera by EIA indicated that the immune response to the vaccine was directed toward epitopes on both gp120 and gp41. Seroresponses to the immunodominant epitopes on gp41 were infrequent and none were detected to the neutralization epitope in the V3 region of gp120. This highly sensitive EIA is useful for characterizing HIV-1-specific antibody responses induced by an HIV-1 gp160 subunit vaccine.     

Taking the HIV (AIDS) test: how to help yourself. National Institute of Allergy and Infectious Diseases

Guidelines are given for those who are considering being tested for HIV. Risk factors that should be considered include unprotected sex, sex with individuals whose HIV status is unknown, and intravenous drug use. Questions for the test facility include confidentiality and counseling availability.     

Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial

BACKGROUND: An objective of the first efficacy trial of a candidate vaccine containing recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein 120 (rgp120) antigens was to assess correlations between antibody responses to rgp120 and the incidence of HIV-1 infection. METHODS: Within the randomized trial (for vaccinees, n=3598; for placebo recipients, n=1805), binding and neutralizing antibody responses to rgp120 were quantitated. A case-cohort design was used to study correlations between antibody levels and HIV-1 incidence. RESULTS: Peak antibody levels were significantly inversely correlated with HIV-1 incidence. The relative risk (RR) of infection was 0.63 (95% confidence interval, 0.45-0.89) per log(10) higher neutralization titer against HIV-1(MN), and the RRs of infection for second-, third-, and fourth-quartile responses of antibody blocking of gp120 binding to soluble CD4 versus first-quartile responses (the lowest responses) were 0.35, 0.28, and 0.22, respectively. CONCLUSIONS: Despite inducing a complex, robust immune response, the vaccine was unable to reduce the incidence of HIV-1. Two interpretations of the correlative results are that the levels of antibodies (i) caused both an increased (low responders) and decreased (high responders) risk of HIV-1 acquisition or (ii) represented a correlate of susceptibility to HIV-1 but had no causal effect on susceptibility. Although the data cannot definitively discriminate between these 2 explanations, (ii) appears to be more likely.     

What you must know about HIV infection in adolescents. National Institute of Allergy and Infectious Diseases

Adolescents are one of the least-studied groups in the AIDS community. The National Institute of Allergy and Infectious Diseases (NIAID) ranks AIDS as the seventh leading cause of death in U.S. children aged 5 to 14, and the sixth leading cause for those aged 15 to 24. Since the average time between initial HIV infection and AIDS is ten years, most of the cases were contracted during adolescence, making education and prevention a high priority in those age groups. Most adolescents were exposed through sexual intercourse or injection drug use. Surveillance data from a 29-State study show that most young men are infected through sex with other men, and most women through heterosexual sex. The Department of Health and Human Services (HHS) has developed several documents on treating HIV in adolescents; the documents are available on the Internet. NIAID supports clinical trials throughout the United States and the National Cancer Institute (NC) conducts clinical research trials for children and adolescents in Bethesda, MD. NCI also provides comprehensive adolescent services through a community-based clinic in Washington, DC.     

The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate vaccine in humans. NIAID AIDS Vaccine Clinical Trials Network

OBJECTIVE: To evaluate the safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant envelope glycoprotein (rgp 160) candidate vaccine in humans. SUBJECTS: Healthy adults (72) who were seronegative for HIV-1 were randomly assigned to one of four groups. INTERVENTIONS: The subjects were randomly assigned to receive 40 or 80 micrograms of rgp 160, 10 micrograms of hepatitis B vaccine, or placebo in three doses (on days 0, 30, and 180), with an elective, nonblinded administration of a fourth dose on day 540. MEASUREMENTS AND MAIN RESULTS: Neither clinical nor laboratory toxicity was encountered during a follow-up period exceeding 21 months. No effect of immunization was noted on lymphocyte counts, mitogenic responses, or delayed-type hypersensitivity. Serum antibody responses to HIV envelope proteins detected by Western blot were seen in 30 of 33 subjects (91%; 95% CI, 71% to 97%) receiving either 40- or 80-micrograms doses of rgp160 and were most commonly of weakly reactive intensity. Responses were first noted by Western blot after the second dose. They markedly increased in frequency after the third dose and declined over the next 12 to 18 months. The administration of a fourth dose resulted in homologous neutralizing activity in sera from 5 to 24 subjects (21%; CI, 7% to 37%) as well as in complement-mediated antibody-dependent enhancement in sera from 6 of 24 subjects (25%; CI, 10% to 42%). Antibody responses were detected by enzyme-linked immunosorbent assay (ELISA) less frequently than by Western blot, and these responses persisted for a shorter time. CONCLUSIONS: The administration of rgp160 was well tolerated and safe, resulted in a high rate of antibody response by Western blot after the administration of the third and fourth doses, and generated serum neutralizing activity and complement-mediated antibody-dependent enhancement in some subjects after the fourth dose.     

A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

This study was designed to compare the effectiveness of fluconazole vs. itraconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. HIV-infected patients who had been successfully treated (achieved negative culture of CSF) for a first episode of cryptococcal meningitis were randomized to receive fluconazole or itraconazole, both at 200 mg/d, for 12 months. The study was stopped prematurely on the recommendation of an independent Data Safety and Monitoring Board. At the time, 13 (23%) of 57 itraconazole recipients had experienced culture-positive relapse, compared with 2 relapses (4%) noted among 51 fluconazole recipients (P = .006). The factor best associated with relapse was the patient having not received flucytosine during the initial 2 weeks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; P = .04). Fluconazole remains the treatment of choice for maintenance therapy for AIDS-associated cryptococcal disease. Flucytosine may contribute to the prevention of relapse if used during the first 2 weeks of primary therapy.     

Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group.

Although fungal urinary tract infections are an increasing nosocomial problem, the significance of funguria is still not clear. This multicenter prospective surveillance study of 861 patients was undertaken to define the epidemiology, management, and outcomes of funguria. Diabetes mellitus was present in 39% of patients, urinary tract abnormalities in 37.7%, and malignancy in 22.2%; only 10.9% had no underlying illnesses. Concomitant nonfungal infections were present in 85%, 90% had received antimicrobial agents, and 83.2% had urinary tract drainage devices. Candida albicans was found in 51.8% of patients and Candida glabrata in 15.6%. Microbiological and clinical outcomes were documented for 530 (61.6%) of the 861 patients. No specific therapy for funguria was given to 155 patients, and the yeast cleared from the urine of 117 (75.5%) of them. Of the 116 patients who had a catheter removed as the only treatment, the funguria cleared in 41 (35.3%). Antifungal therapy was given to 259 patients, eradicating funguria in 130 (50.2%). The rate of eradication with fluconazole was 45.5%, and with amphotericin B bladder irrigation it was 54.4%. Only 7 patients (1.3%) had documented candidemia. The mortality rate was 19.8%, reflecting the multiple serious underlying illnesses found in these patients with funguria.     

From the National Institute of Allergy and Infectious Diseases. Summary of the 19th United States-Japan Joint Cholera Conference

Classical cholera has reappeared in Asia after a 20-year hiatus, reminding us that we still have much to learn about the epidemiology of this disease. The unexpected recovery of V. cholerae from nonendemic estuarine waters suggests that the continued occurrence of clinical cholera may not be entirely dependent on repeated contamination of environmental waters by man. Of critical importance has been the discovery and partial characterization of new enterotoxins produced by V. cholerae and ETEC, a finding that further complicates the already complex problem of fully elucidating the virulence mechanism of these organisms. The recent purification of Shiga toxin is beginning to provide clues as to its structure, function, and possible pathogenic role in EPEC-related hemorrhagic colitis and diarrhea. The conversion of virulent V. cholerae into less virulent strains by genetic engineering provides hope for the ultimate development of safe and effective live oral cholera vaccines. Intestinal Peyer's patches process living and killed enteropathogens differently, and this discovery may afford insights into ways to improve antigen potency. Enterotoxins differ fundamentally in their biochemical effects, and not all of them evoke active electrolyte secretion by altering cyclic-nucleotide levels in mucosal cells. Finally, the mucosal response to a protein toxin may be under some genetic control. The complete proceedings of this conference will be published by KTK Publishers (Tokyo). The next Joint Conference on Cholera has been scheduled for early November 1984 in Nara, Japan.     

HIV-1 virologic and immunologic progression and initiation of antiretroviral therapy among HIV-1-infected subjects in a trial of the efficacy of recombinant glycoprotein 120 vaccine

The first trial of the efficacy of a human immunodeficiency virus (HIV)-1 vaccine was conducted in North America and The Netherlands between 1998 and 2003. This multicenter, randomized, placebo-controlled trial of a recombinant glycoprotein 120 vaccine included 5403 initially HIV-negative volunteers who were monitored for 3 years. The 368 subjects who acquired HIV-1 infection were monitored for 2 years by use of the following postinfection end points: plasma HIV-1 RNA level (viral load), CD4+ lymphocyte count, initiation of antiretroviral therapy (ART), and HIV-1-related clinical outcomes. This article reports the study results that pertain to the effect of vaccination on the postinfection end points. The time until initiation of ART and the time until virologic failure or initiation of ART were similar in the vaccine arm and the placebo arm. The pre-ART viral load and CD4+ lymphocyte count trajectories were also comparable between the groups. Evidently, the vaccine did not affect HIV-1 disease progression.     

Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group.

A multicenter, double-blind, randomized, placebo-controlled clinical trial was conducted to determine the safety and efficacy of thalidomide for treating esophageal aphthous ulceration in persons infected with human immunodeficiency virus (HIV). Twenty-four HIV-infected patients with biopsy-confirmed aphthous ulceration of the esophagus were randomly assigned to receive either oral thalidomide, 200 mg/day, or oral placebo daily for 4 weeks. Eight (73%) of 11 patients randomized to receive thalidomide had complete healing of aphthous ulcers at the 4-week endoscopic evaluation, compared with 3 (23%) of 13 placebo-randomized patients (odds ratio, 13.82; 95% confidence interval, 1.16-823.75; P=.033). Odynophagia and impaired eating ability caused by esophageal aphthae were improved markedly by thalidomide treatment. Adverse events among patients receiving thalidomide included somnolence (4 patients), rash (2 patients), and peripheral sensory neuropathy (3 patients). Thalidomide is effective in healing aphthous ulceration of the esophagus in patients infected with HIV.     

Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Investigators.

OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo-controlled, partially double-blinded multicenter study. SETTING: Adult AIDS Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma HIV-1 RNA level at weeks 24 and 48.RESULTS: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy.     

Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group.

Management of candiduria is limited by the lack of information about its natural history and lack of data from controlled studies on the efficacy of treating it with antimycotic agents. We compared fungal eradication rates among 316 consecutive candiduric (asymptomatic or minimally symptomatic) hospitalized patients treated with fluconazole (200 mg) or placebo daily for 14 days. In an intent-to-treat analysis, candiduria cleared by day 14 in 79 (50%) of 159 receiving fluconazole and 46 (29%) of 157 receiving placebo (P<.001), with higher eradication rates among patients completing 14 days of therapy (P<.0001), including 33 (52%) of 64 catheterized and 42 (78%) of 54 noncatheterized patients. Pretreatment serum creatinine levels were inversely related to candiduria eradication. Fluconazole initially produced high eradication rates, but cultures at 2 weeks revealed similar candiduria rates among treated and untreated patients. Oral fluconazole was safe and effective for short-term eradication of candiduria, especially following catheter removal. Long-term eradication rates were disappointing and not associated with clinical benefit.     

Efficacy testing of recombinant human immunodeficiency virus (HIV) gp160 as a therapeutic vaccine in early-stage HIV-1-infected volunteers. rgp160 Phase II Vaccine Investigators

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.