Modeling how antibody responses may determine the efficacy of COVID-19 vaccines

  • Wouters, O. J. et al. Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation and deployment. Lancet 397, 1023–1034 (2021).


    Google Scholar
     

  • Forni, G. & Mantovani, A. COVID-19 vaccines: where we stand and challenges ahead. Cell Death Differ. 28, 626–639 (2021).


    Google Scholar
     

  • Shrotri, M., Swinnen, T., Kampmann, B. & Parker, E. P. K. An interactive website tracking COVID-19 vaccine development. Lancet Glob. Health 9, e590–e592 (2021).


    Google Scholar
     

  • Koup, R. A. et al. A government-led effort to identify correlates of protection for COVID-19 vaccines. Nat. Med. 27, 1493–1494 (2021).


    Google Scholar
     

  • Saad-Roy, C. M. et al. Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes. Science 372, 363–370 (2021).


    Google Scholar
     

  • Bubar, K. M. et al. Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. Science 371, 916–921 (2021).


    Google Scholar
     

  • Voysey, M. et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet 397, 881–891 (2021).


    Google Scholar
     

  • Garg, A. K., Mittal, S., Padmanabhan, P., Desikan, R. & Dixit, N. M. Increased B cell selection stringency in germinal centers can explain improved COVID-19 vaccine efficacies with low dose prime or delayed boost. Front. Immunol. 12, 776933 (2021).


    Google Scholar
     

  • Tauzin, A. et al. Strong humoral immune responses against SARS-CoV-2 spike after BNT162b2 mRNA vaccination with a 16-week interval between doses. Cell Host Microbe 30, 97–109 (2022).


    Google Scholar
     

  • Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).


    Google Scholar
     

  • Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 Vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).


    Google Scholar
     

  • Logunov, D. Y. et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 397, 671–681 (2021).


    Google Scholar
     

  • Ella, R. et al. Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial. Lancet 398, 2173–2184 (2021).


    Google Scholar
     

  • Jara, A. et al. Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile. N. Engl. J. Med. 385, 875–884 (2021).


    Google Scholar
     

  • Sadoff, J. et al. Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-19. N. Engl. J. Med. 384, 2187–2201 (2021).


    Google Scholar
     

  • Heath, P. T. et al. Safety and efficacy of NVX-CoV2373 COVID-19 vaccine. N. Engl. J. Med. 385, 1172–1183 (2021).


    Google Scholar
     

  • Khoury, D. S. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 27, 1205–1211 (2021).


    Google Scholar
     

  • Earle, K. A. et al. Evidence for antibody as a protective correlate for COVID-19 vaccines. Vaccine 39, 4423–4428 (2021).


    Google Scholar
     

  • Feng, S. et al. Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat. Med. 27, 2032–2040 (2021).


    Google Scholar
     

  • Barrett, J. R. et al. Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses. Nat. Med. 27, 279–288 (2021).


    Google Scholar
     

  • Israelow, B. et al. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2. Sci. Immunol. 6, eabl4509 (2021).


    Google Scholar
     

  • Gilbert, P. B. et al. Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial. Science 375, 43–50 (2022).


    Google Scholar
     

  • Addetia, A. et al. Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with a high attack rate. J. Clin. Microbiol. 58, e02107–e02120 (2020).


    Google Scholar
     

  • Lumley, S. F. et al. Antibody status and incidence of SARS-CoV-2 infection in health care workers. N. Engl. J. Med. 384, 533–540 (2020).


    Google Scholar
     

  • Callow, K. A. Effect of specific humoral immunity and some non-specific factors on resistance of volunteers to respiratory coronavirus infection. J. Hyg. 95, 173–189 (1985).


    Google Scholar
     

  • Liu, L. et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 584, 450–456 (2020).


    Google Scholar
     

  • Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020).


    Google Scholar
     

  • Folegatti, P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396, 467–478 (2020).


    Google Scholar
     

  • Perelson, A. S. & Oster, G. F. Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-non-self discrimination. J. Theor. Biol. 81, 645–670 (1979).

    MathSciNet 

    Google Scholar
     

  • Chi, X. et al. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 369, 650–655 (2020).


    Google Scholar
     

  • Wang, C. et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 11, 2251 (2020).


    Google Scholar
     

  • Seydoux, E. et al. Analysis of a SARS-CoV-2-infected individual reveals development of potent neutralizing antibodies with limited somatic mutation. Immunity 53, 98–105 e105 (2020).


    Google Scholar
     

  • Shi, R. et al. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 584, 120–124 (2020).


    Google Scholar
     

  • Wec, A. Z. et al. Broad neutralization of SARS-related viruses by human monoclonal antibodies. Science 369, 731–736 (2020).


    Google Scholar
     

  • Lei, C. et al. Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. Nat. Commun. 11, 2070 (2020).


    Google Scholar
     

  • Lv, Z. et al. Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody. Science 369, 1505–1509 (2020).


    Google Scholar
     

  • Zost, S. J. et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 443–449 (2020).


    Google Scholar
     

  • Ju, B. et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature 584, 115–119 (2020).


    Google Scholar
     

  • Cao, Y. et al. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell 182, 73–84 (2020).


    Google Scholar
     

  • Hansen, J. et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 369, 1010–1014 (2020).


    Google Scholar
     

  • Rogers, T. F. et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 369, 956–963 (2020).


    Google Scholar
     

  • Barnes, C. O. et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182, 828–842 (2020).


    Google Scholar
     

  • Pinto, D. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 583, 290–295 (2020).


    Google Scholar
     

  • Hanke, L. et al. An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction. Nat. Commun. 11, 4420 (2020).


    Google Scholar
     

  • Webb, N. E., Montefiori, D. C. & Lee, B. Dose–response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies. Nat. Commun. 6, 8443 (2015).


    Google Scholar
     

  • Padmanabhan, P. & Dixit, N. M. Inhibitors of hepatitis C virus entry may be potent ingredients of optimal drug combinations. Proc. Natl Acad. Sci. USA 114, E4524–E4526 (2017).


    Google Scholar
     

  • Jilek, B. L. et al. A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat. Med. 18, 446–451 (2012).


    Google Scholar
     

  • Isho, B. et al. Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Sci. Immunol. 5, eabe5511 (2020).


    Google Scholar
     

  • Iyer, A. S. et al. Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients. Sci. Immunol. 5, eabe0367 (2020).


    Google Scholar
     

  • Röltgen, K. et al. Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Sci. Immunol. 5, eabe0240 (2020).


    Google Scholar
     

  • Shrock, E. et al. Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Science 370, eabd4250 (2020).


    Google Scholar
     

  • Yuan, M. et al. Structural basis of a shared antibody response to SARS-CoV-2. Science 369, 1119–1123 (2020).


    Google Scholar
     

  • Meyer, C. T. et al. Quantifying drug combination synergy along potency and efficacy axes. Cell Syst. 8, 97–108 (2019).


    Google Scholar
     

  • Widge, A. T. et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N. Engl. J. Med. 384, 80–82 (2021).


    Google Scholar
     

  • McMahan, K. et al. Correlates of protection against SARS-CoV-2 in rhesus macaques. Nature 590, 630–634 (2021).


    Google Scholar
     

  • Sette, A. & Crotty, S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 184, 861–880 (2021).


    Google Scholar
     

  • Wölfel, R. et al. Virological assessment of hospitalized patients with COVID-2019. Nature 581, 465–469 (2020).


    Google Scholar
     

  • Neant, N. et al. Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort. Proc. Natl Acad. Sci. USA 118, e2017962118 (2021).


    Google Scholar
     

  • Kissler, S. M. et al. Viral dynamics of acute SARS-CoV-2 infection and applications to diagnostic and public health strategies. PLoS Biol. 19, e3001333 (2021).


    Google Scholar
     

  • Desikan, R., Raja, R. & Dixit, N. M. Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection. PLoS Comput. Biol. 16, e1008064 (2020).


    Google Scholar
     

  • Yu, J. et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 369, 806–811 (2020).


    Google Scholar
     

  • Yang, S., Jerome, K. R., Greninger, A. L., Schiffer, J. T. & Goyal, A. Endogenously produced SARS-CoV-2 specific IgG antibodies may have a limited impact on clearing nasal shedding of virus during primary infection in humans. Viruses 13, 516 (2021).


    Google Scholar
     

  • van Gils, M. J. & Sanders, R. W. In vivo protection by broadly neutralizing HIV antibodies. Trends Microbiol. 22, 550–551 (2014).


    Google Scholar
     

  • Fajnzylber, J. et al. SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nat. Commun. 11, 5493 (2020).


    Google Scholar
     

  • Arnaout, R. et al. SARS-CoV2 testing: the limit of detection matters. Preprint at bioRxiv https://doi.org/10.1101/2020.06.02.131144 (2020).

  • Gonçalves, A. et al. Timing of antiviral treatment initiation is critical to reduce SARS-CoV-2 viral load. CPT Pharmacometrics Syst. Pharm. 9, 509–514 (2020).


    Google Scholar
     

  • Goyal, A., Cardozo-Ojeda, E. F. & Schiffer, J. T. Potency and timing of antiviral therapy as determinants of duration of SARS-CoV-2 shedding and intensity of inflammatory response. Sci. Adv. 6, eabc7112 (2020).


    Google Scholar
     

  • Dagan, N. et al. BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting. N. Engl. J. Med. 384, 1412–1423 (2021).


    Google Scholar
     

  • Walsh, E. E. et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020).


    Google Scholar
     

  • Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adult. N. Engl. J. Med. 383, 2427–2438 (2020).


    Google Scholar
     

  • Maisonnasse, P. et al. COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models. Nat. Commun. 12, 6097 (2021).


    Google Scholar
     

  • Chigutsa, E., O’Brien, L., Ferguson-Sells, L., Long, A. & Chien, J. Population pharmacokinetics and pharmacodynamics of the neutralizing antibodies bamlanivimab and etesevimab in patients with mild to moderate COVID-19 infection. Clin. Pharmacol. Ther. 110, 1302–1310 (2021).


    Google Scholar
     

  • Saha, A. & Dixit, N. M. Pre-existing resistance in the latent reservoir can compromise VRC01 therapy during chronic HIV-1 infection. PLoS Comput. Biol. 16, e1008434 (2020).


    Google Scholar
     

  • Krammer, F. A correlate of protection for SARS-CoV-2 vaccines is urgently needed. Nat. Med. 27, 1147–1148 (2021).


    Google Scholar
     

  • Chatterjee, B., Sandhu, H. S. & Dixit, N. M. The relative strength and timing of innate immune and CD8 T-cell responses underlie the heterogeneous outcomes of SARS-CoV-2 infection. Preprint at medRxiv https://doi.org/10.1101/2021.06.15.21258935 (2021).

  • Padmanabhan, P., Garaigorta, U. & Dixit, N. M. Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment. Nat. Commun. 5, 3872 (2014).


    Google Scholar
     

  • Perelson, A. S. & Ke, R. Mechanistic modeling of SARS-CoV-2 and other infectious diseases and the effects of therapeutics. Clin. Pharmacol. Ther. 109, 829–840 (2020).


    Google Scholar
     

  • Baum, A. et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014–1018 (2020).


    Google Scholar
     

  • Padmanabhan, P. & Dixit, N. M. Modeling suggests a mechanism of synergy between hepatitis C virus entry inhibitors and drugs of other classes. CPT Pharmacometrics Syst. Pharm. 4, 445–453 (2015).


    Google Scholar
     

  • Chou, T. C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharm. Rev. 58, 621–681 (2006).


    Google Scholar
     

  • Padmanabhan, P., Desikan, R. & Dixit, N. M. Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection. PLoS Comput. Biol. 16, e1008461 (2020).


    Google Scholar
     

  • Brouwer, P. J. M. et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science 369, 643–650 (2020).


    Google Scholar
     

  • Kim, K. S. et al. A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2. PLoS Biol. 19, e3001128 (2021).


    Google Scholar
     

  • Zarnitsyna, V. I. et al. Mathematical model reveals the role of memory CD8 T cell populations in recall responses to influenza. Front. Immunol. 7, 165 (2016).


    Google Scholar
     

  • Benotmane, I. et al. Biomarkers of cytokine release syndrome predict disease severity and mortality from COVID-19 in kidney transplant recipients. Transplantation 105, 158–169 (2021).


    Google Scholar
     

  • Ke, R. et al. Daily sampling of early SARS-CoV-2 infection reveals substantial heterogeneity in infectiousness. Preprint at medRxiv https://doi.org/10.1101/2021.07.12.21260208 (2021).

  • Golob, J. L., Lugogo, N., Lauring, A. S. & Lok, A. S. SARS-CoV-2 vaccines: a triumph of science and collaboration. JCI Insight 6, e149187 (2021).


    Google Scholar
     

  • Zhang, Y. et al. Safety, tolerability and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect. Dis. 21, 181–192 (2021).


    Google Scholar
     

  • Jackson, L. A. et al. An mRNA vaccine against SARS-CoV-2—preliminary report. N. Engl. J. Med. 383, 1920–1931 (2020).


    Google Scholar
     

  • Padmanabhan, P., Desikan, R. & Dixit, N. M. COVID-19 vaccine efficacies. Zenodo https://doi.org/10.5281/zenodo.5879304 (2022).