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Background The ALVAC/gp120 + MF59 vaccines in the HIV Vaccine Trials Network (HVTN) 702 efficacy trial did not prevent human immunodeficiency virus-1 (HIV-1) acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. Methods Among 1893 HVTN 702 female vaccinees, 60 HIV-1–seropositive cases and 60 matched seronegative noncases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks after fourth and fifth immunizations. Cox proportional hazards models assessed prespecified responses as predictors of HIV-1 acquisition. Results The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs 40%, P = .03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs 100%, P Conclusions HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T cells with HIV-1 acquisition. Clinical Trials Registration . NCT02968849.

Background HVTN 505 was a human immunodeficiency virus type 1 (HIV-1) preventive vaccine efficacy trial of a DNA/recombinant adenovirus serotype 5 (rAd5) vaccine regimen. We assessed antibody responses measured 1 month after final vaccination (month 7) as correlates of HIV-1 acquisition risk. Methods Binding antibody responses were quantified in serum samples from 25 primary endpoint vaccine cases (diagnosed with HIV-1 infection between month 7 and month 24) and 125 randomly sampled frequency-matched vaccine controls (HIV-1 negative at month 24). We prespecified for a primary analysis tier 6 antibody response biomarkers that measure immunoglobulin G (IgG) and immunoglobulin A (IgA) binding to Env proteins and 2 previously assessed T-cell response biomarkers. Results Envelope-specific IgG responses were significantly correlated with decreased HIV-1 risk. Moreover, the interaction of IgG responses and Env-specific CD8+ T-cell polyfunctionality score had a highly significant association with HIV-1 risk after adjustment for multiple comparisons. Conclusions Vaccinees with higher levels of Env IgG have significantly decreased HIV-1 risk when CD8+ T-cell responses are low. Moreover, vaccinees with high CD8+ T-cell responses generally have low risk, and those with low CD8+ T-cell and low Env antibody responses have high risk. These findings suggest the critical importance of inducing a robust IgG Env response when the CD8+ T-cell response is low., Vaccine-elicited antibodies and T cells correlate with decreased human immunodeficiency virus type 1 (HIV-1) risk in an HIV-1 preventative vaccine efficacy trial of a DNA/recombinant adenovirus serotype 5 (rAd5) vaccine regimen.

Background It is important to identify vaccine-induced immune responses that predict the preventative efficacy of a human immunodeficiency virus (HIV)-1 vaccine. We assessed T-cell response markers as correlates of risk in the HIV Vaccine Trials Network (HVTN) 505 HIV-1 vaccine efficacy trial. Methods 2504 participants were randomized to DNA/rAd5 vaccine or placebo, administered at weeks 0, 4, 8, and 24. Peripheral blood mononuclear cells were obtained at week 26 from all 25 primary endpoint vaccine cases and 125 matched vaccine controls, and stimulated with vaccine-insert-matched peptides. Primary variables were total HIV-1-specific CD4+ T-cell magnitude and Env-specific CD4+ polyfunctionality. Four secondary variables were also assessed. Immune responses were evaluated as predictors of HIV-1 infection among vaccinees using Cox proportional hazards models. Machine learning analyses identified immune response combinations best predicting HIV-1 infection. Results We observed an unexpectedly strong inverse correlation between Env-specific CD8+ immune response magnitude and HIV-1 infection risk (hazard ratio [HR] = 0.18 per SD increment; P = .04) and between Env-specific CD8+ polyfunctionality and infection risk (HR = 0.34 per SD increment; P < .01). Conclusions Further research is needed to determine if these immune responses are predictors of vaccine efficacy or markers of natural resistance to HIV-1 infection.

Using Super Learner, a machine learning statistical method, we assessed varicella zoster virus-specific glycoprotein-based enzyme-linked immunosorbent assay (gpELISA) antibody titer as an individual-level signature of herpes zoster (HZ) risk in the Zostavax Efficacy and Safety Trial. Gender and pre- and postvaccination gpELISA titers had moderate ability to predict whether a 50-59 year old experienced HZ over 1-2 years of follow-up, with equal classification accuracy (cross-validated area under the receiver operator curve = 0.65) for vaccine and placebo recipients. Previous analyses suggested that fold-rise gpELISA titer is a statistical correlate of protection and supported the hypothesis that it is not a mechanistic correlate of protection. Our results also support this hypothesis.

The contribution of host T-cell immunity and HLA class I alleles to the control of human immunodeficiency virus (HIV-1) replication in natural infection is widely recognized. We assessed whether vaccine-induced T-cell immunity, or expression of certain HLA alleles, impacted HIV-1 control after infection in the Step MRKAd5/HIV-1 gag/pol/nef study. Vaccine-induced T cells were associated with reduced plasma viremia, with subjects targeting ≥3 gag peptides presenting with half-log lower mean viral loads than subjects without Gag responses. This effect was stronger in participants infected proximal to vaccination and was independent of our observed association of HLA-B*27, –B*57 and –B*58:01 alleles with lower HIV-1 viremia. These findings support the ability of vaccine-induced T-cell responses to influence postinfection outcome and provide a rationale for the generation of T-cell responses by vaccination to reduce viremia if protection from acquisition is not achieved. Clinical trials identifier: NCT00095576.

Cell-mediated immunity in human immunodeficiency virus (HIV)–infected patients may control viral replication and slow HIV disease progression [1–8]. In preclinical primate models, most vaccines that elicit cell-mediated immunity do not prevent infection, but they do lower post-infection viral loads and slow retroviral disease progression [9–11]. Therefore, a number of HIV-1 vaccine candidates have been developed that aim to elicit cell-mediated immunity. The goal of these vaccines is to improve immune control of viral replication after infection, to decrease HIV-1 RNA levels, and to thereby slow HIV-1 disease progression and reduce sexual transmission to others. The Step study was a randomized trial of the Merck adenovirus type 5 (Ad5) trivalent HIV-1 vaccine that was designed to elicit cell-mediated immunity. Three thousand adults in North America, the Caribbean, South America, and Australia were randomized to receive placebo or the vaccine. Vaccinations were halted and the study was unblinded in 2007, when the first interim analysis indicated that the vaccine would not achieve efficacy for the two primary study end points, HIV-1 acquisition and plasma HIV-1 RNA level 3 months after the diagnosis of HIV infection [12]. In the current analysis, we evaluate the effect of the vaccine on HIV/AIDS disease progression in subjects who became HIV-1–infected during the Step trial. Measures of disease progression include HIV-1 RNA levels, CD4+ T cell counts, time to antiretroviral therapy (ART), and AIDS-free survival during post-infection follow-up [13–15].

Simulation studies were conducted to estimate the statistical power of repeated low-dose challenge experiments performed in nonhuman primates to detect the effect of a candidate human immunodeficiency virus vaccine. The effect of various design parameters on power was explored. Results of simulation studies indicate that repeated low-dose challenge studies with a total sample of size 50 (25 animals/arm) typically provide adequate power to detect a 50% reduction in the per-exposure probability of infection resulting from vaccination. Power generally increases with the maximum number of allowable challenges per animal, the per-exposure risk of infection in control animals, and the proportion of animals susceptible to infection.

A central goal of vaccine research is to identify a vaccine-induced immune response that predicts protection from infection or disease. The term "correlate of protection" has been used to refer to at least 3 distinct concepts, which has resulted in confusion surrounding this topic. We propose precise definitions of these different concepts of immune correlates, using the nomenclature "correlate of risk," "level 1 surrogate of protection," and "level 2 surrogate of protection." We suggest a general framework for assessing these 3 levels of immune correlates in vaccine efficacy trials. To demonstrate the proposed principles, we analyze data from a 1943 influenza vaccine field trial, supporting Weiss strain A-specific antibody titers as a level 1 surrogate of protection. Other real and simulated examples are also discussed.

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 log10 higher neutralization titer against HIV-1MN, 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.

Background The Thai Phase III Trial of ALVAC-HIV and AIDSVAX B/E showed an estimated vaccine efficacy (VE) of 31% to prevent acquisition of human immunodeficiency virus (HIV). Here we evaluated the effect of vaccination on disease progression after infection. Methods CD4(+) T-cell counts and HIV viral load (VL) were measured serially. The primary analysis evaluated vaccine efficacy (VEP) as the percent reduction (vaccine vs placebo) in cumulative probability of a primary composite endpoint of clinical and CD4(+) count components at prespecified time points after infection. Secondary analyses of biomarker-based endpoints were assessed using marginal mean and linear mixed models. Results There were 61 endpoints in the modified intent-to-treat cohort (mITT; n = 114). There was no evidence for efficacy at 30, 42, 54, and 60 months in the mITT and per protocol (n = 90) cohorts. Estimated VEP (mITT) was15.8% (-21.9, 41.8) at 60 months postinfection. There was weak evidence of lower VL and higher CD4(+) count at 60 and 66 months in the vaccine group. Lower mucosal VL was observed among vaccine recipients, primarily in semen (P = .04). Conclusions Vaccination did not affect the clinical course of HIV disease after infection. A potential vaccine effect on the genital mucosa warrants further study.

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.

Candidate human immunodeficiency virus (HIV)-1 vaccines that elicit cytotoxic T lymphocytes may modulate HIV infection, requiring a prototype evaluation to assess participants who become infected with HIV. Of 1497 participants in canarypox HIV-1 vaccine prime-boost trials, 28 (1.9%) acquired HIV-1 infection after vaccination. Median plasma HIV-1 RNA levels (vaccinees, 4.78 log10 copies/mL; placebo recipients, 4.27 log10 copies/mL) and CD4 cell counts (vaccinees, 552 cells/mm3; placebo recipients, 657 cells/mm3) before administration of antiretroviral therapy (ART) and time to a composite end point (plasma HIV-1 RNA level >55,000 copies/mL, CD4 cell count

Maternal plasma human immunodeficiency virus (HIV) type 1 RNA load has a role in perinatal transmission, but significant overlap in the range of plasma virus loads among transmitters and nontransmitters is often observed, which makes it difficult to predict transmission outcome. We measured several virus markers in a drug-naive population of HIV-1-infected mothers in Botswana. Maternal plasma HIV-1 RNA load, peripheral blood mononuclear cell-associated blood HIV-1 DNA load, and cervicovaginal fluid (CVF) HIV-1 DNA load were determined using quantitative real-time polymerase chain reaction. The overall rate of transmission among these mother-infant pairs was 35.7%. Median infant age was 2.5 months. An association between increased plasma HIV-1 RNA load and perinatal transmission was observed (odds ratio [OR], 2.20/1-log virus load; 95% confidence interval [CI], 1.15-4.18). However, the association between increased blood HIV-1 DNA load and perinatal transmission was stronger (OR, 10.30; 95% CI, 2.11-50.38). When blood HIV-1 DNA load was combined with CVF HIV-1 DNA load, the association with transmission increased (OR, 25.0; 95% CI 2.73-228.60).

Initial human immunodeficiency virus (HIV) vaccines are unlikely to prevent acquisition of HIV in all recipients. Moreover, several HIV vaccines are under evaluation that are designed to reduce viremia after acquisition of infection. Such vaccines could provide important benefits to delay HIV progression and to reduce transmission. The decision to license a vaccine on the basis of observed effects on virus load and other postinfection surrogate end points in an efficacy trial is complicated by uncertainty about whether the vaccine effects will persist and reliably predict clinical effects, and by the challenge in interpreting the data posed by treatment of some seroconverters with antiretroviral drugs. Here, we evaluate how analyses of certain surrogate end points can be used for inferring clinically significant vaccine effects and propose end points that could be evaluated in efficacy trials to support licensure. The assessment suggests that a vaccine demonstrating moderately durable effects to delay therapy and to ameliorate viremia merits consideration for licensure.