Statistical evaluation of HIV vaccines in early clinical trials.

The HIV pandemic is a pressing threat to global public health; HIV vaccine development is critical. Clinical evaluation of HIV vaccine candidates differs from the standard therapeutics trial framework primarily due to the fact that healthy individuals are studied. We present an early stage evaluation program developed for the HIV Vaccine Trials Network (HVTN) motivated by characteristics unique to the vaccine setting. The program consists of 3 prototypical stages (Phase I, Ib, II) that provide a unified yet flexible approach to the safety and immunogenicity evaluation of diverse vaccine regimens. The goal of these early trials is to narrow the number of candidate vaccines to the most promising candidates worthy of further study in efficacy trials.

Pox-Protein Public Private Partnership program and upcoming HIV vaccine efficacy trials.

PURPOSE OF REVIEW: The purpose of review is to provide an overview of the Pox-Protein Public Private Partnership (P5) and highlight the progress of the P5 program, including an upcoming HIV vaccine efficacy trial in South Africa. RECENT FINDINGS: The RV144 Thai vaccine efficacy trial was the first to demonstrate that an HIV-1 vaccine can prevent HIV acquisition. The P5 vaccine regimen uses an ALVAC prime and protein boost modeled after the RV144 vaccine and adapted for the subtype C virus predominant in the southern African region. This regimen was recently tested in the HIV Vaccine Trials Network 100 phase 1/2a study in South Africa. Based on prospectively defined immunogenicity thresholds, criteria were met to support the launch of an efficacy study in late 2016. The aim of this phase 2b/3 trial will be to improve upon the results of RV144, with increased and more durable vaccine efficacy, to accelerate the potential licensure of a preventive vaccine in southern Africa. SUMMARY: The planned P5 efficacy trial, HIV Vaccine Trials Network 702, is designed to test and prospectively define correlates of protection, if efficacious. A vaccine with modest efficacy, vaccine efficacy at least 50%, could have substantial public health impact and significantly decrease the incidence of new infections in heavily burdened areas of the world.

Statistical considerations for the design and analysis of the ELISpot assay in HIV-1 vaccine trials.

Effector T lymphocyte responses are considered critical for controlling human immunodeficiency virus type-1 (HIV-1) infection. The enzyme-linked immunospot (ELISpot) assay has emerged as a primary means of assessing HIV-specific T cell responses, and the development of objective methods that distinguish positive and negative ELISpot responses while properly controlling the rate of false positives is critical. In this paper, we consider several statistical methods that are helpful in defining such a positive criterion. Simulation results under a variety of scenarios suggest that a permutation-based criterion using a resampling adjustment for multiple comparisons yields the desired false positive rate while remaining competitive with other potential criteria in terms of sensitivity. These results also provide guidance on the effect of the number of experimental and negative control replicate wells on assay sensitivity. Application of different potential positive criteria using ELISpot assay results from IFN-gamma-secreting T cells of HIV-1 seropositive and seronegative donors confirmed several of the results obtained under simulation. Our findings support the application of statistically-based positive criteria such as the permutation-based resampling approach in assessing HIV vaccine-induced T cell responses. Moreover, the proposed methods have potential utility in related HIV immunopathogenesis studies and in non-HIV clinical vaccine trials.

Phase I/II randomized trial of safety and immunogenicity of LIPO-5 alone, ALVAC-HIV (vCP1452) alone, and ALVAC-HIV (vCP1452) prime/LIPO-5 boost in healthy, HIV-1-uninfected adult participants.

Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 µg), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 µg). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P ≤ 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452)+LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452)+LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited. The clinical trial is registered on ClinicalTrials.gov with registry number NCT00076063.

Novel directions in HIV-1 vaccines revealed from clinical trials.

PURPOSE OF REVIEW: Considerable HIV-1 vaccine development efforts have been deployed over the past decade. Put into perspective, the results from efficacy trials and the identification of correlates of risk have opened large and unforeseen avenues for vaccine development. RECENT FINDINGS: The Thai efficacy trial, RV144, provided the first evidence that HIV-1 vaccine protection against HIV-1 acquisition could be achieved. The correlate of risk analysis showed that IgG antibodies against the gp120 V2 loop inversely correlated with a decreased risk of infection, whereas Env-specific IgA directly correlated with risk. Further clinical trials will focus on testing new envelope subunit proteins formulated with adjuvants capable of inducing higher and more durable functional antibody responses (both binding and broadly neutralizing antibodies). Moreover, vector-based vaccine regimens that can induce cell-mediated immune responses in addition to humoral responses remain a priority. SUMMARY: Future efficacy trials will focus on prevention of HIV-1 transmission in heterosexual population in Africa and MSM in Asia. The recent successes leading to novel directions in HIV-1 vaccine development are a result of collaboration and commitment among vaccine manufacturers, funders, scientists and civil society stakeholders. Sustained and broad collaborative efforts are required to advance new vaccine strategies for higher levels of efficacy.

Accelerating the development of a safe and effective HIV vaccine: HIV vaccine case study for the Decade of Vaccines.

Human immunodeficiency virus (HIV), the etiologic agent that causes AIDS, is the fourth largest killer in the world today. Despite the remarkable achievements in development of anti-retroviral therapies against HIV, and the recent advances in new prevention technologies, the rate of new HIV infections continue to outpace efforts on HIV prevention and control. Thus, the development of a safe and effective vaccine for prevention and control of AIDS remains a global public health priority and the greatest opportunity to eventually end the AIDS pandemic. Currently, there is a renaissance in HIV vaccine development, due in large part to the first demonstration of vaccine induced protection, albeit modest, in human efficacy trials, a generation of improved vaccine candidates advancing in the clinical pipeline, and newly defined targets on HIV for broadly neutralizing antibodies. The main barriers to HIV vaccine development include the global variability of HIV, lack of a validated animal model, lack of correlates of protective immunity, lack of natural protective immune responses against HIV, and the reservoir of infected cells conferred by integration of HIV's genome into the host. Some of these barriers are not unique to HIV, but generic to other variable viral pathogens such as hepatitis C and pandemic influenza. Recommendations to overcome these barriers are presented in this document, including but not limited to expansion of efforts to design immunogens capable of eliciting broadly neutralizing antibodies against HIV, expansion of clinical research capabilities to assess multiple immunogens concurrently with comprehensive immune monitoring, increased support for translational vaccine research, and engaging industry as full partners in vaccine discovery and development.

Safety and immunogenicity of cytotoxic T-lymphocyte poly-epitope, DNA plasmid (EP HIV-1090) vaccine in healthy, human immunodeficiency virus type 1 (HIV-1)-uninfected adults.

We evaluated EP HIV-1090 vaccine, a DNA plasmid encoding 21 cytotoxic T-lymphocyte (CTL) epitopes of human immunodeficiency virus type 1 (HIV-1) and the pan-DR helper T-lymphocyte epitope (PADRE), in a dose escalation, randomized, double-blinded, placebo-controlled Phase 1 trial. Vaccine, at 0.5, 2.0, or 4.0mg doses, or placebo was injected four times over 6 months. Forty-two healthy, HIV-1-uninfected adults were enrolled. Using an interferon-gamma ELISPOT assay, a response to PADRE was detected in one vaccine recipient. Three vaccine recipients raised anti-HIV-1 CD8+ CTL measured by chromium-release assay. The vaccine was safe and well-tolerated, but only weakly immunogenic.

Phase 2 study of an HIV-1 canarypox vaccine (vCP1452) alone and in combination with rgp120: negative results fail to trigger a phase 3 correlates trial.

BACKGROUND: A goal of T-cell HIV vaccines is to define the correlation between a vaccine-induced immune response and protection from HIV infection. We conducted a phase 2 trial to determine if a canarypox vaccine candidate (vCP1452) administered with rgp120 subunit protein would "qualify" for a trial to define a correlate of efficacy. METHODS: A total of 330 healthy volunteers were enrolled into 4 groups: 120 received vCP1452 alone (0, 1, 3, and 6 months), 120 received vCP1452 with 2 different regimens of rgp120 coadministration, and 90 received placebo. HIV-specific antibody responses were measured by enzyme-linked immunoassay (ELISA) and neutralizing activity. T-cell responses were measured by chromium release and interferon-gamma (IFNgamma) enzyme-linked immunospot (ELISpot) assay. RESULTS: Significant neutralizing antibody responses to the HIV MN strain were detected in all vaccine groups, with net responses ranging from 57% (95% confidence interval [CI]: 40% to 71%) to 94% (95% CI: 85% to 99%). Net cumulative HIV-specific CD8 IFNgamma ELISpot assay responses were 13% (95% CI: -1% to 26%) for recipients of vCP1452 alone and 16% (95% CI: 2% to 29%) for recipients of vCP1452 plus rgp120. CONCLUSIONS: Overall, the HIV-specific CD8 cytotoxic T lymphocyte (CTL) response was not sufficient to qualify the regimen for a subsequent trial designed to detect an immune correlate of protection requiring a minimum CD8 CTL frequency of 30%.

Moving to human immunodeficiency virus type 1 vaccine efficacy trials: defining T cell responses as potential correlates of immunity.

There is evidence in both simian immunodeficiency virus and human immunodeficiency virus (HIV) type 1 infection that class I major histocompatibility complex-restricted CD8(+) cytotoxic T lymphocytes play a pivotal role in controlling infection and, potentially, in protecting by immunization. Progress has been made in designing strategies to elicit these responses with HIV-1 vaccines, but methods to reproducibly quantify them have posed difficulties. An interferon-gamma enzyme-linked immunospot assay, using peptide pools spanning the HIV-1 genes, was developed and standardized. This method is rapid (2 days), sensitive (threshold of detection, > or =0.005%), quantitative, feasible using cryopreserved cells, and able to define epitope specificities. When this assay was applied to 36 HIV-1-seropositive and 10 HIV-1-seronegative subjects, it proved to be robust (specificity, 100%). When responses in natural infection were compared with vaccine-induced responses, vaccine recipient responses were > or =1 log lower, which confirms the importance of using this sensitive assay as an initial screen in vaccine protocols.