Analysis of the HIV Vaccine Trials Network 702 Phase 2b-3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk.

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 < .001; Pmag < .001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P ≤.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint). 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.

Designing a Study of Correlates of Risk for Ebola Vaccination.

The recombinant vesicular stomatitis virus (rVSV) Ebola vaccine was shown to be very efficacious in a novel ring vaccination trial in Guinea. However, no correlates of vaccine protection have been established for Ebola vaccines. Several Ebola vaccine candidates are available, but conducting randomized trials of additional candidates in outbreaks is difficult. Establishing correlates of vaccine protection is essential. Here we explore power and sample-size calculations to evaluate potential correlates of risk during an Ebola vaccination campaign in an outbreak. The method requires that a blood draw be made at a predetermined time after vaccination. The statistical analysis estimates the relative risk of the Ebola endpoint occurring from after the blood draw through to the end of follow-up, contrasting vaccine recipients with different values of the immune response marker. The analysis can be done assuming a trichotomous or continuous marker. Under certain assumptions, at an overall vaccine efficacy of 75%, 50 Ebola endpoints in the vaccinees provided good power. At an overall vaccine efficacy of 90%, 20 Ebola endpoints gave good power. Power was highest when more vaccinees were in the high- and low-responder groups versus the middle group and when vaccine efficacy differed the most between the high- and low-responder groups.

Higher T-Cell Responses Induced by DNA/rAd5 HIV-1 Preventive Vaccine Are Associated With Lower HIV-1 Infection Risk in an Efficacy Trial.

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.

Lessons from the RV144 Thai phase III HIV-1 vaccine trial and the search for correlates of protection.

RV144 remains the only HIV-1 vaccine trial to demonstrate efficacy against HIV-1 acquisition. The prespecified analysis of immune correlates of risk showed that antibodies directed against the V1V2 region of gp120, in particular the IgG1 and IgG3 subclass mediating antibody-dependent cell-mediated cytotoxicity, seem to play a predominant role in protection against HIV-1 acquisition and that plasma envelope (Env)-specific IgA antibodies were directly correlated with risk. RV144 and recent nonhuman primate challenge studies suggest that Env is essential, and perhaps sufficient, to induce protective antibody responses against mucosal HIV-1 acquisition. Follow-up clinical trials are ongoing to further dissect the immune responses elicited by the RV144 ALVAC-HIV and AIDSVAX® B/E regimen. The study of gp120 Env immunogens and immune correlates of risk has resulted in the development of improved antigens. Whether the RV144 immune correlates of risk will generalize to other populations vaccinated with similar immunogens with different modes and intensity of transmission remains to be demonstrated. Efficacy trials are now planned in heterosexual populations in southern Africa and men who have sex with men in Thailand.

Human newborn bacille Calmette-Guérin vaccination and risk of tuberculosis disease: a case-control study.

BACKGROUND: An incomplete understanding of the immunological mechanisms underlying protection against tuberculosis (TB) hampers the development of new vaccines against TB. We aimed to define host correlates of prospective risk of TB disease following bacille Calmette-Guérin (BCG) vaccination. METHODS: In this study, 5,726 infants vaccinated with BCG at birth were enrolled. Host responses in blood collected at 10 weeks of age were compared between infants who developed pulmonary TB disease during 2 years of follow-up (cases) and those who remained healthy (controls). RESULTS: Comprehensive gene expression and cellular and soluble marker analysis failed to identify a correlate of risk. We showed that distinct host responses after BCG vaccination may be the reason: two major clusters of gene expression, with different myeloid and lymphoid activation and inflammatory patterns, were evident when all infants were examined together. Cases from each cluster demonstrated distinct patterns of gene expression, which were confirmed by cellular assays. CONCLUSIONS: Distinct patterns of host responses to Mycobacterium bovis BCG suggest that novel TB vaccines may also elicit distinct patterns of host responses. This diversity should be considered in future TB vaccine development.

Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.

BACKGROUND: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models. METHODS: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions. FINDINGS: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker. INTERPRETATION: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen. FUNDING: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.

A systematic review on correlates of risk of TB disease in children and adults.

BACKGROUND: Tuberculosis (TB) remains one of the leading causes of death in the world. Targeted treatment to prevent progression from TB exposure and infection to disease is a key element of WHO End-TB strategy. A systematic review to identify and develop correlates of risk (COR) of TB disease is timely. METHOD: EMBASE, MEDLINE, PUBMED were searched using relevant keywords and MeSH terms published between 2000 and 2020 on COR of TB disease in children and adults. Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) framework was used for structuring and reporting of outcomes. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2). RESULTS: 4105 studies were identified. Following eligibility screening, 27 studies were quality assessed. Risk of bias was high in all studies. Broad variations in COR type, study population, methodology and result reporting were observed. Tuberculin skin test (TST) and interferon gamma release essays (IGRA) are poor COR. Transcriptomic signatures although promising require validation studies to assess wider applicability. Performance consistency of other CORs-cell marker, cytokines and metabolites are much needed. CONCLUSION: This review identifies the need for a standardized approach to identify a universally applicable COR signature to achieve the WHO END-TB targets.

Generating Survival Times Using Cox Proportional Hazards Models with Cyclic and Piecewise Time-Varying Covariates.

Time-to-event outcomes with cyclic time-varying covariates are frequently encountered in biomedical studies that involve multiple or repeated administrations of an intervention. In this paper, we propose approaches to generating event times for Cox proportional hazards models with both time-invariant covariates and a continuous cyclic and piecewise time-varying covariate. Values of the latter covariate change over time through cycles of interventions and its relationship with hazard differs before and after a threshold within each cycle. The simulations of data are based on inverting the cumulative hazard function and a log link function for relating the hazard function to the covariates. We consider closed-form derivations with the baseline hazard following the exponential, Weibull, or Gompertz distribution. We propose two simulation approaches: one based on simulating survival data under a single-dose regimen first before data are aggregated over multiple-dosing cycles and another based on simulating survival data directly under a multiple-dose regimen. We consider both fixed intervals and varying intervals of the drug administration schedule. The method's validity is assessed in simulation experiments. The results indicate that the proposed procedures perform well in generating data that conform to their cyclic nature and assumptions of the Cox proportional hazards model.

Novel prime-boost vaccine strategies against HIV-1.

Introduction: Given the complexities of HIV infection and the HIV genetic heterogeneity, a successful HIV vaccine should elicit broad adaptive and innate immune responses. Vaccine prime-boost platforms may achieve this goal. Several factors including selection of antigen, type of vector, delivery route, dose, adjuvant, boosting regimen, order of vector injection, and intervals between vaccinations influence the outcome. Areas covered: We reviewed the literature on the latest findings of the various prime-boost HIV vaccine clinical trials, with particular emphasis on the most advanced and promising strategies. Expert opinion: Data suggest that heterologous may be better than homologous prime-boost regimens for protection. The most advanced strategies to have reached efficacy trials use either canarypox vector (ALVAC) boosted by adjuvanted gp120 protein or adenovirus (Ad26) vector expressing mosaic antigens boosted by gp140 protein. DNA prime and vectors and/or protein boost regimens are at less advanced development stage. These regimens, while imperfect (efficacy ≥50%), could contribute substantially to the control of HIV epidemics as a part of a comprehensive HIV prevention program. To ensure prompt vaccine access in populations with the greatest need, attention should be given to post-efficacy activities necessary to achieve appropriate uptake and implementation of effective vaccines.

Immune correlates of protection for dengue: State of the art and research agenda.

Dengue viruses (DENV1-4) are mosquito-borne flaviviruses estimated to cause up to ∼400 million infections and ∼100 million dengue cases each year. Factors that contribute to protection from and risk of dengue and severe dengue disease have been studied extensively but are still not fully understood. Results from Phase 3 vaccine efficacy trials have recently become available for one vaccine candidate, now licensed for use in several countries, and more Phase 2 and 3 studies of additional vaccine candidates are ongoing, making these issues all the more urgent and timely. At the "Summit on Dengue Immune Correlates of Protection", held in Annecy, France, on March 8-9, 2016, dengue experts from diverse fields came together to discuss the current understanding of the immune response to and protection from DENV infection and disease, identify key unanswered questions, discuss data on immune correlates and plans for comparison of results across assays/consortia, and propose a research agenda for investigation of dengue immune correlates, all in the context of both natural infection studies and vaccine trials.

Tricks to translating TB transcriptomics.

Transcriptomics and other high-throughput methods are increasingly applied to questions relating to tuberculosis (TB) pathogenesis. Whole blood transcriptomics has repeatedly been applied to define correlates of TB risk and has produced new insight into the late stage of disease pathogenesis. In a novel approach, authors of a recently published study in Science Translational Medicine applied complex data analysis of existing TB transcriptomic datasets, and in vitro models, in an attempt to identify correlates of protection in TB, which are crucially required for the development of novel TB diagnostics and therapeutics to halt this global epidemic. Utilizing latent TB infection (LTBI) as a surrogate of protection, they identified IL-32 as a mediator of interferon gamma (IFNγ)-vitamin D dependent antimicrobial immunity and a marker of LTBI. Here, we provide a review of all TB whole-blood transcriptomic studies to date in the context of identifying correlates of protection, discuss potential pitfalls of combining complex analyses originating from such studies, the importance of detailed metadata to interpret differential patient classification algorithms, the effect of differing circulating cell populations between patient groups on the interpretation of resulting biomarkers and we decipher weighted gene co-expression network analysis (WGCNA), a recently developed systems biology tool which holds promise of identifying novel pathway interactions in disease pathogenesis. In conclusion, we propose the development of an integrated OMICS platform and open access to detailed metadata, in order for the TB research community to leverage the vast array of OMICS data being generated with the aim of unraveling the holy grail of TB research: correlates of protection.

An HIV Vaccine for South-East Asia-Opportunities and Challenges.

Recent advances in HIV vaccine development along with a better understanding of the immune correlates of risk have emerged from the RV144 efficacy trial conducted in Thailand. Epidemiological data suggest that CRF01_AE is still predominant in South-East Asia and is spreading in China with a growing number of circulating recombinant forms due to increasing human contact, particularly in large urban centers, tourist locations and in sites of common infrastructure. A vaccine countering CRF01_AE is a priority for the region. An Asia HIV vaccine against expanding B/E or BCE recombinant forms should be actively pursued. A major challenge that remains is the conduct of efficacy trials in heterosexual populations in this region. Men who have sex with men represent the main target population for future efficacy trials in Asia. Coupling HIV vaccines with other prevention modalities in efficacy trials might also be envisaged. These new avenues will only be made possible through the conduct of large-scale efficacy trials, interdisciplinary teams, international collaborations, and strong political and community commitments.