John G. McNeil

Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand

BACKGROUND The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. METHODS In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. RESULTS In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P=0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. CONCLUSIONS This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)

A new circulating recombinant form, CRF15_01B, reinforces the linkage between IDU and heterosexual epidemics in Thailand.

HIV-1 subtype B and CRF01_AE have been in circulation in Thailand and Southeast Asia for more than a decade. Initially separated by risk group, the two strains are increasingly intermixed, and two recombinant strains of essentially reciprocal structure have been recently reported. Here we identify additional CRF_01B recombinants and provide the evidence that HIV-1 strains now pass freely between the two high-risk populations. HIV isolates that showed discordance between CRF01_AE and subtype B in multi-region genotyping assays were selected for the study. They were drawn from 3 different cohorts in Thailand representing different risk behaviors and demographic characteristics: a drug user cohort in the north, a family planning clinic attendee cohort in the southeast, and a cohort study of the mucosal virology and immunology of HIV-1 infection in Thailand. The DNA from these isolates was PCR amplified to recover the full HIV-1 genome and subjected to sequencing and phylogenetic analysis. We establish that one particular CRF_01B recombinant, with the external envelope of subtype B and the rest of the genome from CRF01_AE, is circulating widely in Thailand. Termed CRF15_01B (also referred to as CRF15), the strain was primarily heterosexually transmitted, although injecting drug use (IDU) also played a role. In aggregate data from the studies, CRF15 constituted 1.7% of all HIV-1 infections (95% confidence interval 0.5-4.4%) and was dispersed widely in the country. The previously separate heterosexual and IDU epidemics have apparently been bridged by a new CRF. The entry of CRF15 into the mainstream of the epidemic signals new complexity in the long stable molecular picture in Thailand. These recombinants must be considered in ongoing or projected efficacy evaluations of HIV-1 vaccines and antiviral therapies.

Declining prevalence of HIV-1 infection in young Thai men.

ObjectiveTo evaluate trends in HIV-1 seroprevalence in Thailand. DesignHIV-1 serosurvey of successive cohorts of young Thai men entering service with the Royal Thai Army (RTA) between November 1989 and November 1994. MethodsIn November 1989, the RTA Medical Department began routine HIV-1-antibody screening of men who were selected by lottery for conscription. Between November 1989 and November 1994, 311 108 young men were screened at induction. Demographic data were collected between November 1991 and May 1993 and again in November 1994. ResultsThe seroprevalence of HIV-1 among conscripts nationwide increased rapidly from 0.5% in 1989 to 3.5% in 1992 and reached 3.7% in 1993. In 1994, the overall prevalence decreased to 3.0%. The decrease was greatest in the upper North (from 12.4% in 1992 to 7.9% in 1994), where the prevalence has been the highest. However, decreases were observed in men from all regions of residence in the country, from both rural and urban areas, and at all educational levels. ConclusionsThe decline in prevalence suggests declining incidence and that HIV control programs in Thailand are having an impact on the HIV epidemic.

A phase 1/2 comparative vaccine trial of the safety and immunogenicity of a CRF01_AE (subtype E) candidate vaccine: ALVAC-HIV (vCP1521) prime with oligomeric gp160 (92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) boost.

Background:The development of an effective HIV-1 vaccine is critical to control the pandemic. A prime-boost HIV-1 vaccine trial assessing safety and immunogenicity was conducted in Thailand as part of an evaluation of candidate regimens for a phase 3 efficacy trial. Methods:ALVAC-HIV (vCP1521), expressing circulating recombinant form 01_AE (CRF01_AE) gp120/subtype B LAI and subtype B Gag/Protease boosted with recombinant envelope oligomeric CRF01_AE gp160 (ogp160) or bivalent CRF01_AE/subtype B gp120 CM235/SF2, was evaluated in a phase 1/II trial of 130 HIV-negative Thai adults. Results:One hundred forty volunteers were enrolled, and 130 completed all safety and immunogenicity visits. Reactogenicity was common but generally mild, and there was no significant difference in the adverse event rate between vaccine and placebo recipients (P = 0.26). There were 7 serious adverse events during the follow-up period, none of which were vaccine related. Cumulative HIV-specific, CD8-mediated, cytotoxic T-lymphocyte responses were observed in 11 (25%) of 44 subjects who received ALVAC boosted by bivalent gp120 and in 5 (11%) of 45 subjects who received ALVAC boosted by ogp160, but these differences were not statistically significant compared with those in placebo recipients (P = 0.62 and P = 0.37, respectively). HIV-specific lymphoproliferative responses were detected in 84% of subunit-boosted vaccine recipients and in 10% of placebo recipients. Neutralizing antibody responses to CRF01_AE and subtype B laboratory strains were seen in 95% of ogp160-boosted and 100% of gp120 B/E-boosted vaccinees, respectively. Conclusions:These 2 different prime-boost regimens seem to be safe and displayed cell-mediated immune responses consistent with those in other trials of canarypox vectors.

A phase I/II trial of HIV SF2 gp120/MF59 vaccine in seronegative Thais.

Abstract Fifty-two human immunodeficiency virus type 1, seronegative Thai adults from the community were enrolled in a double-blind, placebo controlled, phase I/II trial of HIV SF2 gp120/MF59 vaccine to determine the safety and immunogenicity of this recombinant, B clade, HIV envelope protein vaccine. Twenty-six subjects were enrolled at each of two sites in Thailand, Bangkok and Chiang Mai. Twelve subjects received placebo and 40 subjects received vaccine (50 μg). Subjects were immunized according to one of two schedules, 0, 1 and 4 or 0, 1 and 6 months. The frequency of adverse reactions was not different between placebo and vaccine subjects, nor between immunization schedules. Of vaccinees, all developed high-titer binding antibody to the immunogen (rgp120), 39 developed neutralizing antibody (NA) responses against homologous virus (HIV-1SF2), and 22 developed NA against heterologous virus (HIV-1MN). No subject demonstrated intercurrent HIV infection, however screening EIA reactivity occurred in 27% of recipients. Thus, this candidate HIV vaccine was found to be safe and immunogenic in Thai adults, laying the foundation for development of a subtype E construct in this population.

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.

Direct measurement of human immunodeficiency virus seroconversions in a serially tested population of young adults in the United States Army, October 1985 to October 1987

Direct measurement of the incidence of infection with the human immunodeficiency virus (HIV)--the rate of new HIV infection--is vital if we are to understand better the dynamics of the current epidemic of HIV infection. Because soldiers are periodically and routinely screened for antibody to HIV, it is possible to measure the incidence of HIV infection directly in this large, demographically well-characterized population of young adults. To determine the incidence of HIV infection in this population, we examined test results reported by the U.S. Armys routine antibody-screening programs. During the first two years of the screening programs, the observed incidence of HIV infection was approximately 0.77 per 1000 persons per year. This rate was higher than expected on the basis of previously published estimates of seroprevalence in the Army (approximately 1.50 per 1000). On the basis of this annual incidence, and assuming it to be stable, we estimate that approximately 600 soldiers will become infected with HIV each year. The observed rate in the Army may be lower than the incidence of HIV infection in the corresponding demographic groups within the general U.S. population.

Evaluation of behavioral and social issues among Thai HIV vaccine trial volunteers.

Behavioral and social issues were investigated in phase I/II preventive HIV vaccine trial volunteers in Thailand. These included risk behavior, HIV knowledge, distress, and social experiences associated with trial participation. Data were collected at baseline and at 4- and 8-month follow-up visits. Volunteers reported relatively low levels of risk behaviors at baseline and at the follow-up visits. About one fifth reported overtly negative reactions from family or friends. No problems with discrimination in employment, health care, or insurance were reported. Findings add to the evidence suggesting the feasibility of phase I/II prophylactic HIV vaccine trials with low-risk volunteers in Thailand.

Incidence of Hiv-1 Infection Among Young Men in Thailand

SummaryRoyal Thai Army (RTA) enlistees were tested for HIV-1 seropositivity prospectively in order to explore their feasibility as a cohort in an HIV-1 preventive vaccine efficacy trial. The 17,615 seronegative enlistees, virtually all 21-year-old men, contributed 10,409 person-years (p-y) of follow-up. Cohorts were enlisted in November 1991 and May 1992 from northern Thailand and Bangkok. The follow-up rate was 50%, with loss to follow-up significantly associated with location of the base, marital status, and educational level. Seroincidence was 0.5/100 p-y for recruits stationed in Bangkok, 1.0/100 p-y in the lower north, and 3.2/100 p-y in the upper north. In a multiple regression model, the young mans birthplace was strongly associated with risk of infection, suggesting that transmission occurred during leave as well as during duty. Incidence rates were significantly lower in those who were married at the time of enlistment and in those with 3