Positive-unlabeled Learning to Infer Protection Status and Identify Correlates in Vaccine Efficacy Field Trials

Overview

Journal iScience

Publisher Cell Press

Date 2024 Sep 19

PMID 39295637

Authors

Shiwei Xu

Natasha S Kelkar

Margaret E Ackerman

Affiliations

Soon will be listed here.

Abstract

Correlates of protection (CoPs) are key guideposts that both support vaccine development and licensure as well as improve our understanding of the attributes of immune responses that may directly provide protection. Unfortunately, factors such as low rate of exposure and low efficacy can result in low power to discover correlates in field trials-making it difficult to identify these guideposts for the pathogens against which there is greatest need for further insights. To address this gap, we examine the ability of positive-unlabeled (PU) learning approaches to use immunogenicity data and infection status outcomes to accurately predict protection status. We report a combination of PU bagging and two-step reliable negative techniques that accurately classify the protection status of unlabeled (uninfected) samples from synthetic and real-world humoral immune response profiles in human trials and animal models and lead to the discovery of CoPs that are "missed" using conventional infection status case-control analysis.

Citing Articles

Plasmodium vivax antigen candidate prediction improves with the addition of Plasmodium falciparum data.

Chou R, Ouattara A, Takala-Harrison S, Cummings M NPJ Syst Biol Appl. 2024; 10(1):133.

PMID: 39537634 PMC: 11561111. DOI: 10.1038/s41540-024-00465-y.

References

Pittala S, Bagley K, Schwartz J, Brown E, Weiner J, Prado I . Antibody Fab-Fc properties outperform titer in predictive models of SIV vaccine-induced protection. Mol Syst Biol. 2019; 15(5):e8747. PMC: 6497031. DOI: 10.15252/msb.20188747. View

Jiang H, Zhang L, Li J, Zhu F . Next Steps for Efficacy Evaluation in Clinical Trials of COVID-19 Vaccines. Engineering (Beijing). 2021; 7(7):903-907. PMC: 8186691. DOI: 10.1016/j.eng.2021.04.013. View

Karasavvas N, Billings E, Rao M, Williams C, Zolla-Pazner S, Bailer R . The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120. AIDS Res Hum Retroviruses. 2012; 28(11):1444-57. PMC: 3484815. DOI: 10.1089/aid.2012.0103. View

Zeng X, Zhong Y, Lin W, Zou Q . Predicting disease-associated circular RNAs using deep forests combined with positive-unlabeled learning methods. Brief Bioinform. 2019; 21(4):1425-1436. DOI: 10.1093/bib/bbz080. View

Yang P, Li X, Mei J, Kwoh C, Ng S . Positive-unlabeled learning for disease gene identification. Bioinformatics. 2012; 28(20):2640-7. PMC: 3467748. DOI: 10.1093/bioinformatics/bts504. View

B Gilbert P, Donis R, Koup R, Fong Y, Plotkin S, Follmann D . A Covid-19 Milestone Attained - A Correlate of Protection for Vaccines. N Engl J Med. 2022; 387(24):2203-2206. DOI: 10.1056/NEJMp2211314. View

Dunning A . A model for immunological correlates of protection. Stat Med. 2005; 25(9):1485-97. DOI: 10.1002/sim.2282. View

Plotkin S, B Gilbert P . Nomenclature for immune correlates of protection after vaccination. Clin Infect Dis. 2012; 54(11):1615-7. PMC: 3348952. DOI: 10.1093/cid/cis238. View

Virtanen P, Gommers R, Oliphant T, Haberland M, Reddy T, Cournapeau D . SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat Methods. 2020; 17(3):261-272. PMC: 7056644. DOI: 10.1038/s41592-019-0686-2. View

10.

Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R . Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009; 361(23):2209-20. DOI: 10.1056/NEJMoa0908492. View

11.

Felber B, Lu Z, Hu X, Valentin A, Rosati M, Remmel C . Co-immunization of DNA and Protein in the Same Anatomical Sites Induces Superior Protective Immune Responses against SHIV Challenge. Cell Rep. 2020; 31(6):107624. PMC: 7329227. DOI: 10.1016/j.celrep.2020.107624. View

12.

Seaton K, Huang Y, Karuna S, Heptinstall J, Brackett C, Chiong K . Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition. EBioMedicine. 2023; 93:104590. PMC: 10363420. DOI: 10.1016/j.ebiom.2023.104590. View

13.

Kolosov N, Daly M, Artomov M . Prioritization of disease genes from GWAS using ensemble-based positive-unlabeled learning. Eur J Hum Genet. 2021; 29(10):1527-1535. PMC: 8484264. DOI: 10.1038/s41431-021-00930-w. View

14.

Corey L, B Gilbert P, Juraska M, Montefiori D, Morris L, Karuna S . Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition. N Engl J Med. 2021; 384(11):1003-1014. PMC: 8189692. DOI: 10.1056/NEJMoa2031738. View

15.

Rolland M, Tovanabutra S, deCamp A, Frahm N, B Gilbert P, Sanders-Buell E . Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial. Nat Med. 2011; 17(3):366-71. PMC: 3053571. DOI: 10.1038/nm.2316. View

16.

Zheng Y, Peng H, Zhang X, Zhao Z, Gao X, Li J . DDI-PULearn: a positive-unlabeled learning method for large-scale prediction of drug-drug interactions. BMC Bioinformatics. 2019; 20(Suppl 19):661. PMC: 6929327. DOI: 10.1186/s12859-019-3214-6. View

17.

Nguni T, Chasara C, Ndhlovu Z . Major Scientific Hurdles in HIV Vaccine Development: Historical Perspective and Future Directions. Front Immunol. 2020; 11:590780. PMC: 7655734. DOI: 10.3389/fimmu.2020.590780. View

18.

Ackerman M, Das J, Pittala S, Broge T, Linde C, Suscovich T . Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV. Nat Med. 2018; 24(10):1590-1598. PMC: 6482471. DOI: 10.1038/s41591-018-0161-0. View

19.

Lakhashe S, Amacker M, Hariraju D, Vyas H, Morrison K, Weiner J . Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges. Front Immunol. 2022; 13:788619. PMC: 8902080. DOI: 10.3389/fimmu.2022.788619. View

20.

Ju Z, Wang S . Computational Identification of Lysine Glutarylation Sites Using Positive-Unlabeled Learning. Curr Genomics. 2020; 21(3):204-211. PMC: 7521029. DOI: 10.2174/1389202921666200511072327. View