Assessing correlates of protection in vaccine trials: statistical solutions in the context of high vaccine efficacy

Abstract Objectives The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro, A., and F. Tibaldi. 2019. “Assessing Correlates of Protection in Vaccine Trials: Statistical Solutions in the Context of High Vaccine Efficacy.” BMC Medical Research Methodology 19: 47 showed that the rare infections observed in the vaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and meta-analysis. The objective of this work is to investigate the impact of this problem on another statistical method for the assessment of CoPs called Principal stratification. Methods We perform simulation experiments to investigate the effect of high vaccine efficacy on the performance of the Principal Stratification approach. Results Similarly to the Prentice framework, simulation results show that the power of the Principal Stratification approach decreases when the VE grows. Conclusions It can be challenging to validate principal surrogates (and statistical surrogates) for vaccines with very high vaccine efficacy.

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The O-Ag Antibody Response to Francisella Is Distinct in Rodents and Higher Animals and Can Serve as a Correlate of Protection

Pathogens ◽

10.3390/pathogens10121646 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1646

Author(s):

Lauren E. Shoudy ◽

Prachi Namjoshi ◽

Gabriela Giordano ◽

Sudeep Kumar ◽

Jennifer D. Bowling ◽

...

Keyword(s):

Vaccine Efficacy ◽

Low Dose ◽

High Sensitivity ◽

High Dose ◽

Live Vaccine Strain ◽

Plasma Samples ◽

Vaccine Candidates ◽

Correlates Of Protection ◽

Vaccine Trials ◽

Bona Fide

Identifying correlates of protection (COPs) for vaccines against lethal human (Hu) pathogens, such as Francisella tularensis (Ft), is problematic, as clinical trials are currently untenable and the relevance of various animal models can be controversial. Previously, Hu trials with the live vaccine strain (LVS) demonstrated ~80% vaccine efficacy against low dose (~50 CFU) challenge; however, protection deteriorated with higher challenge doses (~2000 CFU of SchuS4) and no COPs were established. Here, we describe our efforts to develop clinically relevant, humoral COPs applicable to high-dose, aerosol challenge with S4. First, our serosurvey of LVS-vaccinated Hu and animals revealed that rabbits (Rbs), but not rodents, recapitulate the Hu O-Ag dependent Ab response to Ft. Next, we assayed Rbs immunized with distinct S4-based vaccine candidates (S4ΔclpB, S4ΔguaBA, and S4ΔaroD) and found that, across multiple vaccines, the %O-Ag dep Ab trended with vaccine efficacy. Among S4ΔguaBA-vaccinated Rbs, the %O-Ag dep Ab in pre-challenge plasma was significantly higher in survivors than in non-survivors; a cut-off of >70% O-Ag dep Ab predicted survival with high sensitivity and specificity. Finally, we found this COP in 80% of LVS-vaccinated Hu plasma samples as expected for a vaccine with 80% Hu efficacy. Collectively, the %O-Ag dep Ab response is a bona fide COP for S4ΔguaBA-vaccinated Rb and holds significant promise for guiding vaccine trials with higher animals.

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Epitope-Specific Serological Assays for RSV: Conformation Matters

Vaccines ◽

10.3390/vaccines7010023 ◽

2019 ◽

Vol 7 (1) ◽

pp. 23 ◽

Cited By ~ 11

Author(s):

Emily Phung ◽

Lauren Chang ◽

Kaitlyn Morabito ◽

Masaru Kanekiyo ◽

Man Chen ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Antigenic Site ◽

Immune Monitoring ◽

Effective Vaccine ◽

F Protein ◽

Correlates Of Protection ◽

Vaccine Trials ◽

Antigenic Sites ◽

Syncytial Virus ◽

The Impact

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in children and older adults. An effective vaccine must elicit neutralizing antibodies targeting the RSV fusion (F) protein, which exists in two major conformations, pre-fusion (pre-F) and post-fusion (post-F). Although 50% of the surface is shared, pre-F contains highly neutralization-sensitive antigenic sites not present on post-F. Recent advancement of several subunit F-based vaccine trials has spurred interest in quantifying and understanding the protective potential of antibodies directed to individual antigenic sites. Monoclonal antibody competition ELISAs are being used to measure these endpoints, but the impact of F conformation and competition from antibodies binding to adjacent antigenic sites has not been thoroughly investigated. Since this information is critical for interpreting clinical trial outcomes and defining serological correlates of protection, we optimized assays to evaluate D25-competing antibodies (DCA) to antigenic site Ø on pre-F, and compared readouts of palivizumab-competing antibodies (PCA) to site II on both pre-F and post-F. We show that antibodies to adjacent antigenic sites can contribute to DCA and PCA readouts, and that cross-competition from non-targeted sites is especially confounding when PCA is measured using a post-F substrate. While measuring DCA and PCA levels may be useful to delineate the role of antibodies targeting the apex and side of the F protein, respectively, the assay limitations and caveats should be considered when conducting immune monitoring during vaccine trials and defining correlates of protection.

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The Impact of Serotype Cross-Protection on Vaccine Trials: DENVax as a Case Study

Vaccines ◽

10.3390/vaccines8040674 ◽

2020 ◽

Vol 8 (4) ◽

pp. 674

Author(s):

Maíra Aguiar ◽

Nico Stollenwerk

Keyword(s):

Vaccine Efficacy ◽

Careful Consideration ◽

Dengue Vaccine ◽

Serious Adverse Events ◽

Post Vaccination ◽

Vaccine Trials ◽

Long Time ◽

Health Need ◽

The Impact ◽

Over Time

There is a growing public health need for effective preventive interventions against dengue, and a safe, effective and affordable dengue vaccine against the four serotypes would be a significant achievement for disease prevention and control. Two tetravalent dengue vaccines, Dengvaxia (CYD-TDV—Sanofi Pasteur) and DENVax (TAK 003—Takeda Pharmaceutical Company), have now completed phase 3 clinical trials. Although Dengvaxia resulted in serious adverse events and had to be restricted to individuals with prior dengue infections, DENVax has shown, at first glance, some encouraging results. Using the available data for the TAK 003 trial, we estimate, via the Bayesian approach, vaccine efficacy (VE) of the post-vaccination surveillance periods of 12 and 18 months. Although better measurement over a long time was expected for the second part of the post-vaccination surveillance, variation in serotype-specific efficacy needs careful consideration. Besides observing that individual serostatus prior to vaccination is determinant of DENVax vaccine efficacy, such as for Dengvaxia, we also noted, after comparing the VE estimations for 12- and 18-month periods, that vaccine efficacy is decreasing over time. The comparison of efficacies over time is informative and very important, and brings up the discussion of the role of temporary cross-immunity in dengue vaccine trials and the impact of serostatus prior to vaccination in the context of dengue fever epidemiology.

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Distinguishing Causation from Correlation in the Use of Correlates of Protection to Evaluate and Develop Influenza Vaccines

American Journal of Epidemiology ◽

10.1093/aje/kwz227 ◽

2019 ◽

Vol 189 (3) ◽

pp. 185-192 ◽

Cited By ~ 1

Author(s):

Wey Wen Lim ◽

Nancy H L Leung ◽

Sheena G Sullivan ◽

Eric J Tchetgen Tchetgen ◽

Benjamin J Cowling

Keyword(s):

Vaccine Efficacy ◽

Vaccine Development ◽

Influenza Vaccines ◽

Protective Effects ◽

Immune Markers ◽

Immune Marker ◽

Correlates Of Protection ◽

Rational Vaccine Design ◽

Individual Protection ◽

Protection Against Infection

Abstract There is increasing attention to the need to identify new immune markers for the evaluation of existing and new influenza vaccines. Immune markers that could predict individual protection against infection and disease, commonly called correlates of protection (CoPs), play an important role in vaccine development and licensing. Here, we discuss the epidemiologic considerations when evaluating immune markers as potential CoPs for influenza vaccines and emphasize the distinction between correlation and causation. While an immune marker that correlates well with protection from infection can be used as a predictor of vaccine efficacy, it should be distinguished from an immune marker that plays a mechanistic role in conferring protection against a clinical endpoint—the latter might be a more reliable predictor of vaccine efficacy and a more appropriate target for rational vaccine design. To clearly distinguish mechanistic and nonmechanistic CoPs, we suggest using the term “correlates of protection” for nonmechanistic CoPs, and ‘‘mediators of protection’’ for mechanistic CoPs. Furthermore, because the interactions among and relative importance of correlates or mediators of protection can vary according to age or prior vaccine experience, the effect sizes and thresholds for protective effects for CoPs could also vary in different segments of the population.

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Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial

Clinical and Vaccine Immunology ◽

10.1128/cvi.00604-15 ◽

2016 ◽

Vol 23 (3) ◽

pp. 228-235 ◽

Cited By ~ 31

Author(s):

Andrew J. Dunning ◽

Carlos A. DiazGranados ◽

Timothy Voloshen ◽

Branda Hu ◽

Victoria A. Landolfi ◽

...

Keyword(s):

Influenza Vaccine ◽

Vaccine Efficacy ◽

Standard Dose ◽

The Elderly ◽

High Dose ◽

Efficacy Trial ◽

Correlates Of Protection ◽

Immune Correlates ◽

Immunologic Assays ◽

Dose Vaccine

ABSTRACTAlthough a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children, data on immune protection in the elderly are sparse. A recent vaccine efficacy trial comparing standard-dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness. The high-dose vaccine induced significantly higher antibody titers than the standard-dose vaccine for all assays. For the hemagglutination inhibition assay, a titer of 40 was found to correspond with 50% protection when the assay virus was antigenically well matched to the circulating virus—the same titer as is generally recognized for 50% protection in younger adults. A dramatically higher titer was required for 50% protection when the assay virus was a poor match to the circulating virus. With the well-matched virus, some protection was seen at the lowest titers; with the poorly matched virus, high levels of protection were not achieved even at the highest titers. Strong associations were also seen between virus neutralization test titers and protection, but reliable estimates for 50% protection were not obtained. An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection; in particular, the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01427309.)

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Third Shot vaccination for COVID-19 in Israel

Medical & Clinical Research ◽

10.33140/mcr.06.033 ◽

2021 ◽

Vol 6 ◽

Keyword(s):

Clinical Trials ◽

Vaccine Efficacy ◽

Vaccination Campaign ◽

Vaccine Delivery ◽

Vaccine Effectiveness ◽

High Quality ◽

Equitable Distribution ◽

Correlates Of Protection ◽

Scientific Questions ◽

Global Population

After several manufacturers announced COVID-19 vaccine efficacy in clinical trials for disease, a comprehensive post-efficacy strategy for the following steps to ensure vaccination of the global population is now required. These considerations should include: how to manufacture billions of doses of high-quality vaccines, support for vaccine purchase, coordination of supply, the equitable distribution of vaccines, and the logistics of global vaccine delivery, all of which are a prelude to a massive vaccination campaign targeting people of all ages. Furthermore, additional scientific questions about the vaccines remain, and that should be answered to improve vaccine efficacy, including questions regarding the optimization of vaccination regimens, booster doses, the correlates of protection, vaccine effectiveness, safety, and enhanced surveillance. The timely and coordinated execution of these post-efficacy tasks will bring the pandemic effective and efficient [1].

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Complex immune correlates of protection in HIV-1 vaccine efficacy trials

Immunological Reviews ◽

10.1111/imr.12514 ◽

2017 ◽

Vol 275 (1) ◽

pp. 245-261 ◽

Cited By ~ 62

Author(s):

Georgia D. Tomaras ◽

Stanley A. Plotkin

Keyword(s):

Vaccine Efficacy ◽

Correlates Of Protection ◽

Immune Correlates ◽

Efficacy Trials ◽

Hiv 1

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Prediction of pertussis vaccine efficacy using a correlates of protection model

Vaccine ◽

10.1016/j.vaccine.2008.04.016 ◽

2008 ◽

Vol 26 (27-28) ◽

pp. 3516-3521 ◽

Cited By ~ 16

Author(s):

Robert C. Kohberger ◽

David Jemiolo ◽

Fernando Noriega

Keyword(s):

Pertussis Vaccine ◽

Vaccine Efficacy ◽

Correlates Of Protection

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Preimmunization correlates of protection shared across malaria vaccine trials in adults

npj Vaccines ◽

10.1038/s41541-021-00425-1 ◽

2022 ◽

Vol 7 (1) ◽

Author(s):

Maxwell L. Neal ◽

Fergal J. Duffy ◽

Ying Du ◽

John D. Aitchison ◽

Kenneth D. Stuart

Keyword(s):

Malaria Vaccine ◽

Effective Vaccine ◽

Vaccine Response ◽

Correlates Of Protection ◽

Vaccine Trials ◽

Or Groups ◽

Immunological Mechanisms ◽

Functional Profiling ◽

Inflammatory State ◽

Baseline Characteristics

AbstractIdentifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.

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