Several immunogens induce HIV-specific neutralization and in vitro lymphoproliferation in adults at low HIV-1 risk, but responses in persons at high HIV-1 risk are not known. We performed a multicenter, double-blinded, adjuvant-controlled trial with two gp120 vaccines in 296 HIV-1-uninfected volunteers, including 176 reporting higher HIV-1 risk activities. The immunogens were remarkably well tolerated. After three immunizations, 210 of 241 vaccinees (87%) developed neutralizing antibodies, which persisted in 59% after 2 years. The injection drug users receiving SF-2/gp120 had decreased antibody responses relative to the lower risk groups. Envelope-specific lymphoproliferation peaked after two immunizations, and 54% of vaccinees mounted a DTH reaction to gp120 after 4 years. In summary, these immunogens have low adverse reactogenicity and induce durable antibody and T cell responses to the prototype strains. Unexpected differences in antibody responses among diverse HIV-1 risk strata lend support to the conduct of expanded phase II trials in populations other than low-risk volunteers.

Effective human immunodeficiency virus (HIV) vaccination may require induction of neutralizing antibodies (NAs) and CD8+ cytotoxic T lymphocytes (CTL) to prevent transmission and control early infection. Recombinant envelope proteins induce NAs but rarely CD8+ CTL responses, and vaccinia vectors containing HIV-1 envelope elicit CD8+ cytotoxicity but few NAs. To benefit from both approaches, 56 vaccinia-naive subjects were randomized to a regimen of priming with recombinant vaccinia gp160LAI and boosting with recombinant gp120SF-2, gp120LAI, gp120MN, or gp160MN. Of 51 persons for whom assays were done, 26 demonstrated envelope-specific CTL. Boosting with gp120, compared with gp160, elicited significantly more NAs and CD4-blocking antibodies. Neutralization of the homologous and heterologous HIV-1 laboratory strains occurred in all subjects receiving vac/env and gp120 and was detectable in 91% of the subjects for >6 months. Thus, vaccine regimens in which one component elicits primarily CTL and the other NAs offer promise for the development of an effective HIV-1 vaccine strategy.

Proviral sequences were determined and immunologic characterization was carried out for envelope glycoproteins from 7 vaccinees who became infected with human immunodeficiency virus type 1 (HIV-1), through high-risk behavior, while participating in clinical trials of MN-rgp120, a candidate HIV-1 vaccine. All 7 infections resulted from subtype B viruses; however, only 3 of the viruses possessed the MN serotype-defining V3 domain sequence, IGPGRAF, prevalent in 60%-70% of US infections, Six of the 7 viruses differed from MN-rgp120 at a neutralizing epitope in the C4 domain, and all 7 differed from MN-rgp120 at a neutralizing epitope in the V2 domain. Recombinant gp120 was prepared from each breakthrough specimen and tested for binding to a panel of neutralizing monoclonal antibodies, The results suggest that 6 of 7 breakthrough infections may be related to incomplete immunization or to infection with viruses that differed from the vaccine immunogen at important virus-neutralizing epitopes.

A recombinant human immunodeficiency virus 1 IIIB (HIV-1IIIB) gp120 subunit vaccine (IIIB-rgp120/HIV-1, Genentech) was tested for safety and immunogenicity in a randomised, double-blind, placebo-controlled phase-I trial. HIV-1-seronegative adult volunteers received three 100 micrograms or 300 micrograms doses of IIIB-rgp120/HIV-1 in alum adjuvant (10 vaccinees in each group), or alum adjuvant alone (8 vaccinees), at 0, 4, and 32 weeks by intramuscular injection. The three injections were well tolerated in both vaccine groups. Antibodies that neutralised homologous HIV-1IIIB were induced in 9 of 10 recipients after three 300 micrograms doses, and 6 of these 9 sera also neutralised heterologous HIV-1SF2. A dose response was evident, since three 100 micrograms injections induced lower titres of HIV-1IIIB neutralising antibodies and in fewer recipients (5 of 9) than the higher dose, with no neutralisation of HIV-1SF2. Similarly, syncytia-inhibiting, CD4-rgp120-blocking, and HIV-1IIIB V3-binding antibodies were induced in a dose dependent manner. Response to the 300 micrograms per dose vaccination occurred in a larger proportion of volunteers and at higher mean titres than seen in previous human trials with other recombinant envelope subunit vaccines or live vaccinia-env priming followed by envelope subunit boosting.

AIDS Research and Human RetrovirusesVol. 8, No. 8 Specific Activation Strategies for Amplification of Low CTL SignalsKENT J. WEINHOLD, J. TARTAGLIA, E. PAOLETTI, B. GRAHAM, D. SCHWARTZ, J. McELRATH, N. ROBERTS, and G. GORSEKENT J. WEINHOLDSearch for more papers by this author, J. TARTAGLIASearch for more papers by this author, E. PAOLETTISearch for more papers by this author, B. GRAHAMSearch for more papers by this author, D. SCHWARTZSearch for more papers by this author, J. McELRATHSearch for more papers by this author, N. ROBERTSSearch for more papers by this author, and G. GORSESearch for more papers by this authorPublished Online:16 Mar 2009https://doi.org/10.1089/aid.1992.8.1373AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "Specific Activation Strategies for Amplification of Low CTL Signals." , 8(8), p. 1373FiguresReferencesRelatedDetailsCited byHIV Type 1 Vaccine-Induced Cytotoxic T Cell Responses in Phase I Clinical Trials: Detection, Characterization, and Quantitation M. JULIANA McELRATH, ROBERT F. SILICIANO, and KENT J. WEINHOLD15 March 2009 | AIDS Research and Human Retroviruses, Vol. 13, No. 3 Volume 8Issue 8Aug 1992 To cite this article:KENT J. WEINHOLD, J. TARTAGLIA, E. PAOLETTI, B. GRAHAM, D. SCHWARTZ, J. McELRATH, N. ROBERTS, and G. GORSE.Specific Activation Strategies for Amplification of Low CTL Signals.AIDS Research and Human Retroviruses.Aug 1992.1373-1373.http://doi.org/10.1089/aid.1992.8.1373Published in Volume: 8 Issue 8: March 16, 2009PDF download

We evaluated the toxicity and efficacy of netilmicin and tobramycin in 89 older adults with serious bacterial infections and pre-existing renal impairment in a prospective, blinded, randomized trial. Complete resolution or improvement of infection occurred at 34/36 (94%) evaluable sites in netilmicin-treated patients and at 26/31 (84%) evaluable sites in tobramycin-treated patients. 10/44 (23%) netilmicin- and 7/45 (16%) tobramycin-treated patients experienced nephrotoxicity during treatment. The mean serum creatinine level improved significantly at the end of therapy compared to pre-treatment in those patients who did not experience nephrotoxicity in both treatment groups. 5/19 (26%) netilmicin-treated patients and 2/18 (11%) tobramycin-treated patients assessable for ototoxicity experienced decrements in auditory thresholds. Ototoxic netilmicin-treated patients had higher serum netilmicin levels than did non-ototoxic patients. Patients who experienced ototoxicity were not more likely to have experienced nephrotoxicity. The rates of toxicity were not statistically different and were similar to those seen in studies of patients with normal pre-treatment renal function.

OBJECTIVE:To ascertain current infection control practices, endoscope cleaning procedures, perceived risks of infection, and implementation of universal precautions in gastrointestinal endoscopy units in the United States.DESIGN:National mailed survey of gastroenterology nurses and associates conducted anonymously in March 1988.SETTING:Completed surveys were received from all 50 states and Puerto Rico and from all practice settings. The most common practice setting was private/community hospitals (66%).PARTICIPANTS:Of the 4,952 survey forms mailed to all members and to interested nonmembers of the Society of Gastrointestinal Nurses and Associates, 2, 158 (44%) were returned and 2,030 (41%) were completed and evaluable. Of the respondents, 1,487 (73%) were registered nurses.RESULTS:Sixty-seven percent (n = 1,358) of the respondents routinely used an enzymatic cleaner as a step in the instrument decontamination process; 93% (n = 1,879) chemically disinfected instruments after each case; and 88% (n = 1,779) disinfected endoscopes with an aqueous glutaraldehyde product. Respondents reported that they and a significantly smaller proportion of physicians (p less than .001) employed barrier precautions for all endoscopic cases involving possible contact with blood/body fluids of patients known (66% versus 57%, respectively) and not known (12% versus 8%, respectively) to have a bloodborne infection. Endoscopy-related infections, usually bacterial, were reported to have occurred at their institutions by 6% (n = 116) of respondents.CONCLUSIONS:We conclude that cleaning, disinfection, and sterilization procedures for gastrointestinal endoscopic instruments vary, that appropriate protective apparel is not always worn, and that some practices may lead to preventable endoscopy-related infection in patients.

To study the association of malnutrition with nosocomial infection in a general medical and surgical inpatient population, we retrospectively compared 45 patients with nosocomial infection to 45 uninfected control patients, matched using several nonnutritional variables known to predispose to nosocomial infection. Univariate and multivariate analyses were done. Poor nutritional score (derived from serum albumin, total lymphocyte count, and unintentional body weight loss), unintentional body weight loss, low serum albumin level at both time of admission and the first nosocomial infection, and worsening in the nutritional score and serum albumin from admission to the first nosocomial infection were associated with the development of nosocomial infection. Nutritional factors were more abnormal in subgroups of patients with nosocomial pneumonia, urinary tract infection, wound infection, and bacteremia than in controls. The findings suggest that further study of correlations between nutritional factors and nosocomial infections is needed.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.