Request for "Correlate of Protection" prefix IRI additions

[lnanderson]

Requester: @lnanderson [ORCID:0000-0002-8741-7823]; last updated on 2023-03-24T19:53:25+00:00. Requested Assignee: @yongqunh

Request for additional prefix IRIs to be included at the Vaccine Ontology collection in expanding "correlate of protection (CoP)" terms, defined and extracted from both Plotkin and Gilbert literature references, as a complimentary extension to VO:0000857, VO:0000858, VO:0000859. Definition source reference citations include: Qin et al. (2007) [PMID:17922394], Gilbert, Qin, & Self (2008) [PMID:17979212], Plotkin (2010) [PMID:20463105], and Plotkin & Gilbert (2012) [PMID:22437237] and should be referred to in the descriptions outlined in the table below.

Additionally, an iteration of the mRNA-1273 vaccine (COVID-19 RNA vaccine) was identified in Gilbert et al. (2022) [PMID:34812653], as provided in the clinicaltrials.gov data source collection accession NCT04470427, to be included with complimentary subClass prefix IRIs VO:0005277 (mRNA-1273.211, "Moderna TX ID: mRNA-12732-P205"), VO:0005415 (mRNA-1273.214, "Moderna TX ID: mRNA-1273-P306"), VO:0005233 (mRNA-1273.351, "Moderna TX ID: mRNA-1273-P201"), and VO:0005416 (mRNA-1273.529, "Moderna TX ID: mRNA-1273-P305").

preferred_name	Synonyms	definitions	definition_source	requester_comments
correlate of protection	CoP, mCoP, nCoP, immunological biomarker, predictive biomarker, validated immune biomarker	An immune marker statistically correlated with vaccine efficacy (equivalently predictive of vaccine efficacy) that may or may not be a mechanistic causal agent of protection. A correlate of protection can be used to accurately predict the level of vaccine efficacy conferred to vaccine recipients (individuals or subgroups defined by the immune marker level). Note: The terms are nested in that mechanistic correlates of protection (mCoPs) and non-mechanistic correlate of protection (nCoPs) are CoPs. Moreover, mCoPs and nCoPs are mutually exclusive and exhaustive, such that a CoP is either an mCoP or an nCoP.	PMID:22437237, PMID:34812653, PMID:36849083	suggested new subClass: predictive biomarker (biomarkers)
mechanistic correlate of protection	mCoP, causal agent of protection, protective immune function	a correlate of protection in the nomenclature of Plotkin [PMID:11176570, PMID:18558875, PMID:20463105], where a CoP is mechanistically and causally responsible for protection.	PMID:22437237	suggested subClass: correlate of protection
nonmechanistic correlate of protection	nCoP, correlate of protection not causal, predictor of protection not causal	a surrogate in the nomenclature of Plotkin [PMID:11176570, PMID:18558875, PMID:20463105], where a CoP that is not a mechanistic causal agent of protection.	PMID:22437237	suggested subClass: correlate of protection
correlate of risk	CoR, Correlate of Risk	CoR is an immune marker statistically associated with the rate of the clinical end point used for measuring efficacy in the vaccine or control group. A CoR in the vaccine group is hypothesized to be a CoP, but may not be if the CoR merely marks pathogen exposure or intrinsic biological susceptibility to the clinical end point in a way not manipulable by vaccination (the risk of these CoP failures can be minimized by controlling for known exposure and natural resistance factors in the statistical assessment of CoRs). *Note: Statistical assessment of CoPs in a vaccine efficacy trial is preceded by assessment of “correlates of risk (CoRs)” in the trial (Qin terminology)[PMID:17922394], in which a CoR is an immune marker statistically associated with the rate of the clinical end point used for measuring efficacy in the vaccine or control group.	PMID:22437237, PMID:34812653	suggested new subClass: risk marker (TBD)
specific correlate of protection	Specific CoP, level 1 surrogate of protection (SoP1), SoP statistical, SoP principal	a specific surrogate of protection in the nomenclature of Qin et al [PMID:17922394].	PMID:22437237	suggested subClass: correlate of protection
bridging correlate of protection	Bridging CoP, level 2 surrogate of protection (SoP2), general CoP	a general surrogate of protection in the nomenclature of Qin et al [PMID:17922394].	PMID:22437237	suggested subClass: correlate of protection
surrogate of protection	SoP, Surrogate of Protection	An immune response that substitutes for the true immunologic correlate of protection, which may be unknown or not easily measurable.	PMID:20463105	suggested new subClass: surrogate marker (biomarkers)
absolute correlate		A specific level of response highly correlated with protection; a threshold.	PMID:20463105	suggested subClass: surrogate marker
relative correlate		A level of response variably correlated with protection.	PMID:20463105	suggested subClass: surrogate marker
cocorrelate		One of two or more factors that correlate with protection in alternative, additive, or synergistic ways.	PMID:20463105	suggested subClass: TBD
mRNA-1273	Moderna TX ID: mRNA-1273-P301, mRNA-1273 COVID-19 vaccine, COVE phase 3 trial	The mRNA-1273 vaccine is being developed to prevent COVID-19, the disease resulting from Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) infection. The study is designed to primarily evaluate the efficacy, safety, and immunogenicity of mRNA-1273 to prevent COVID-19 for up to 2 years after the second dose of mRNA-1273.	PMID:34812653;	suggested subClass of: COVID-19 RNA vaccine

[djinnome]

The terms "level 1 surrogate of protection" and "level 2 surrogate of protection" have been deprecated and renamed to "specific correlate of protection" and "bridging correlate of protection", respectively in this publication:

Plotkin SA, Gilbert PB. Nomenclature for immune correlates of protection after vaccination. Clin Infect Dis. 2012 Jun;54(11):1615-7. doi: 10.1093/cid/cis238. Epub 2012 Mar 20. PMID: 22437237; PMCID: PMC3348952.

They provide mappings between these old terms and the new terms here:

1. The terms are nested in that mechanistic correlates of protection (mCoPs) and nonmechanistic correlate of protection (nCoPs) are CoPs. Moreover, mCoPs and nCoPs are mutually exclusive and exhaustive, such that a CoP is either an mCoP or an nCoP.

2. Mapping of new nomenclature to previous nomenclature: a. Specific CoP = specific surrogate of protection in the nomenclature of Qin et al [1] b. Bridging CoP = general surrogate of protection in the nomenclature of Qin et al c. mCoP = correlate of protection in the nomenclature of Plotkin [2–4] d. nCoP = surrogate in the nomenclature of Plotkin [2–4]

3. Statistical assessment of CoPs in a vaccine efficacy trial is preceded by assessment of “correlates of risk (CoRs)” in the trial (Qin terminology), in which a CoR is an immune marker statistically associated with the rate of the clinical end point used for measuring efficacy in the vaccine or control group. A CoR in the vaccine group is hypothesized to be a CoP, but may not be if the CoR merely marks pathogen exposure or intrinsic biological susceptibility to the clinical end point in a way not manipulable by vaccination (the risk of these CoP failures can be minimized by controlling for known exposure and natural resistance factors in the statistical assessment of CoRs). Moreover, CoRs may be directly statistically assessed as CoPs in efficacy trials in 2 main ways, each of which combines assumptions with CoR analysis. The first approach is based on CoR analyses in each of the vaccine and control groups and on the association of vaccination status on the clinical end point, and assesses the validity of the CoR as a replacement for the clinical end point [5]. The second approach is based on CoR analysis in the vaccine group and on a modified CoR analysis in the control group, which assesses the association between the immune marker that control subjects would have had if they had received vaccine with the rate of the clinical end point. This approach collects additional data in the efficacy trial to predict the vaccine-induced immune marker level in control subjects [6], and assesses how strongly vaccine efficacy varies with this marker level [7]. The first approach applies only for immune markers that vary over a similar range in the vaccine and control groups (thereby not applying in efficacy trials that only enroll pathogen-naive persons), whereas the latter approach applies generally.

[lnanderson]

@djinnome - I have updated the table above to reflect "specific correlate of protection" and "bridging correlate of protection" as the terms representative of the historical depreciation of "Level 1 surrogate of protection" and "Level 2 surrogate of protection" in Qin et al [PMID:17922394].

[cthoyt]

@yongqunh please let us know if you or your team get a chance to look at this

[yongqunh]

@cthoyt Got it. Working on it now. Thanks!

[yongqunh]

@lnanderson and @cthoyt: The suggested terms are good fits for the Vaccine Ontology (VO). However, before we add the terms to VO, I have some questions. The major question is what the parent terms we should use to classify these terms such as 'correlate of protection'. As defined, 'correlate of protection' is "An immune marker statistically correlated with vaccine efficacy (equivalently predictive of vaccine efficacy) that may or may not be a mechanistic causal agent of protection". Now, we need to define what is 'immune marker'.

I assume that immune marker is a biomarker. Then the question is what a biomarker is. In a previous paper: https://ceur-ws.org/Vol-3073/paper8.pdf , we define biomarker as "A material entity that has a measurable quality or process profile(s), which can be used as an indicator of an underlying biological state or identity". I am wondering if you agree on the definition. Afterwards we can then define immune marker and then 'correlate of protection'.

[lnanderson]

@yongqunh and @cthoyt: I agree that an immune marker can be categorized as a biomarker. Instead of creating a new definition for biomarkers, I would suggest adopting the existing term definition for Biomarkers [MESH:D015415] as defined by the Medical Subject Headings Ontology (MESH). If you take a look at the record link, they have already identified the term "Immune Markers" under the "altLabel" list.

Implementing "biomarkers" as a new subclass into the VO collection could potentially allow for additional mapping of a few terms suggested in the table above, which I have adjusted my curation comments to reflect.

[cthoyt]

MeSH is a possibility, but it does not have any formal ontological commitments, nor does it play nicely within the OBO ontology world. Another possibility is to materialize the biomarker concepts proposed in the OGMS paper (described briefly in this recent comment from Chris Mungall) https://github.com/OBOFoundry/OBOFoundry.github.io/pull/2311#issuecomment-1472266588

[yongqunh]

@lnanderson thanks for your comment. MeSH terms are usually not used for ontology reusing purpose because it is not considered as a reference ontology.

The MeSH definition is still discussable. Its definition is: "Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, ENVIRONMENTAL EXPOSURE and its effects, disease diagnosis; METABOLIC PROCESSES; SUBSTANCE ABUSE; PREGNANCY; cell line development; EPIDEMIOLOGIC STUDIES; etc."

Based on our BFO-based ontology scheme, a parameter appears to be a data item. However, I am not sure if it is a good way to define a biomarker as a data item.

[yongqunh]

For example, we may say that Epidermal growth factor (EGF) is a prognostic biomarker in chronic kidney diseases (ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104645/ ). In this case, the EGF is a protein: https://en.wikipedia.org/wiki/Epidermal_growth_factor . Its mRNA expression correlates with estimated glomerular filtration rate (eGFR), which is used to define chronic kidney diseases. In this case, EGF is a protein (material entity), it is not a data item. Meanwhile, its gene expression values predict chronic kidney diseases.

[yongqunh]

This is the 'biomarker' definion in OPMI, which I would suggest using: http://purl.obolibrary.org/obo/OPMI_0000445
"Definition: A material entity that has a measurable quality or process profile(s), which can be used as an indicator of an underlying biological state or identity."

Also, see the reference for more info: https://ceur-ws.org/Vol-3073/paper8.pdf

After we define biomarker is a material entity and immune marker is a biomarker, then we may consider 'correlate of protection' differently. The term 'correlate of protection' may not be a biomarker per se. When we say some geneX's expression correlates with protection, we may say that geneX is the biomarker, and its expression pattern correlates with the protection. So 'correlate of protection' is derived from the biomarker geneX, and itself is not a biomarker.

[lnanderson]

@yongqunh and @cthoyt: This is great feedback.

Here is another resource that is a little more granular and adds to the OPMI reference above, how about http://purl.obolibrary.org/obo/NCIT_C16342 - "A characteristic that can be objectively measured and serves as an indicator for normal biologic processes, pathogenic processes, state of health or disease, the risk for disease development and/or prognosis, or responsiveness to a particular therapeutic intervention." Based on the *Reference Source, we can say the biomarker source determines the biomarker type (e.g., molecular, histologic, radiographic, digital, or physiologic).

*Reference Source: Contents of a Biomarker Description (NBK566059) Glossary Definition: https://www.ncbi.nlm.nih.gov/books/NBK338448/def-item/glossary.biomarker/

For example, neutralizing antibodies (nAbs) or binding antibodies (bAbs) have been established as a correlate of protection for vaccines against many viral diseases. See reference https://doi.org/10.1126/science.abm3425 (Gilbert et al. 2021), where evaluated bAb and nAb markers were described as strongly inversely correlated with COVID-19 risk and directly correlated with vaccine efficacy add evidence toward establishing an immune marker surrogate end point for mRNA COVID-19 vaccines.

"Symptomatic COVID-19 infection can be prevented by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. A “correlate of protection” is a molecular biomarker to measure how much immunity is needed to fight infection and is key for successful global immunization programs. Gilbert et al. determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna COVE phase 3 clinical trial (see the Perspective by Openshaw). By measuring binding and neutralizing antibodies against the viral spike protein, the authors found that the levels of both antibodies correlated with the degree of vaccine efficacy. The higher the antibody level, the greater the protection afforded by the messenger RNA (mRNA) vaccine."

[lnanderson]

@yongqunh and @cthoyt: Following up on the above comment. See below if this seem appropriate to move forward with on "Biomarkers" and "Immune Markers". If so, we can move on to "Correlates of Protection".

1. Biomarker: “A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions. Biomarkers may include molecular, histologic, radiographic, or physiologic characteristics.”

• Reference Source: Contents of a Biomarker Description (NBK566059) • Relevant Term IRI: http://purl.obolibrary.org/obo/NCIT_C16342 • Synonyms: Signature Molecule, biomarker, biological marker, signature molecule, Biological Marker, Biological Markers, Molecular Marker, Biomarker, Marker, molecular marker, Biomarkers • Subtypes: susceptibility/risk biomarker, diagnostic biomarker, monitoring biomarker, prognostic biomarker, predictive biomarker, response biomarker, safety biomarker

2. Immune Markers: “A biomarker that is indicative of an immune response.”

• Reference Source: PMID:34812653, PMID:36658109, PMID:36949083, PMID:30290889, PMID:22072636 • Relevant Term IRI: http://purl.obolibrary.org/obo/OPMI_0000446 • Synonyms: immune correlates, immune surrogates, antibody markers, molecular biomarkers, immune biomarkers • Subtypes: neutralization markers, neutralizing antibodies (“nAbs”), binding markers, binding antibodies (“bAbs”)

[yongqunh]

The newly proposed is a better solution. The definition provided by the reference source and NCIT is a common one that has been widely cited. We have also quoted and commented on the definition in our OPMI paper: https://ceur-ws.org/Vol-3073/paper8.pdf In OPMI, we define biomarker as a material entity. As argued in the paper, it is difficult to define the “characteristic” in BFO-based ontology framework. The difinition of biomarker as a material entity would solve the issue of what is the bottom nature of biomarker.

After further consideration, I would like to propose to generate a new term called “biomarker characteristic (data)”, which can be classified under ‘data item’ or ‘information artifact’ as a measurement data that is used as an indicator of … …”. Then this term can be linked to the material entity biomarker. Both terms can be used but for different purposes. Please see what you would think of this. Thanks.