- May 2021
Choe et al showed that rates of antibody positivity was still high after 8 months, however, neutralizing activity was only detected in 53.4% of asymptomatic or mildly symptomatic participants after 8 months of infection,
Crawford et al: Neutralizing antibody titres (and total antibodies) declined an average of about 4-fold from 1 to 4 months after symptom onset.
Choe PG, Kim KH, Kang CK, et al. Antibody Responses 8 Months after Asymptomatic or Mild SARS-CoV-2 Infection. Emerg Infect Dis. 2021;27(3):928-931. doi:10.3201/eid2703.204543
Katharine H D Crawford, Adam S Dingens, Rachel Eguia, Caitlin R Wolf, Naomi Wilcox, Jennifer K Logue, Kiel Shuey, Amanda M Casto, Brooke Fiala, Samuel Wrenn, Deleah Pettie, Neil P King, Alexander L Greninger, Helen Y Chu, Jesse D Bloom, Dynamics of Neutralizing Antibody Titers in the Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection, The Journal of Infectious Diseases, Volume 223, Issue 2, 15 January 2021, Pages 197–205, https://doi.org/10.1093/infdis/jiaa618
consensus on IgG
Gudbjartsson et al – Study of 30,000 people in Iceland showed that IgG antibodies had not declined by the 4 month mark.
Gudbjartsson DF, Norddahl GL, Melsted P, Gunnarsdottir K, Holm H, Eythorsson E, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. New England Journal of Medicine. 2020;383(18):1724-34.
Garcia-Beltran et al showed that severely ill patients had the highest levels of antibodies. Anti-RBD IgG neutralisation was reduced in severely ill patients. The authors developed an antibody neutralisation potency index to indicate patients more likely to develop severe disease.
Garcia-Beltran WF, Lam EC, Astudillo MG, Yang D, Miller TE, Feldman J, et al. COVID-19-neutralizing antibodies predict disease severity and survival. Cell. 2021;184(2):476-88.e11.
SARS-CoV-2 positive children
Some children present with severe secondary effects in response to COVID-19, similar to Kawasaki disease, termed multisystem inflammatory disease in children (MIS-C). MIS-C patients present with higher frequencies of CD4+ and CD8+ T cells and lower levels of IL-17A, ESDN and TNF-β (1, 2, 3, 4). Additionally, children with MIS-C demonstrate an increase in IgG antibodies but low IgM antibodies (2). Data suggests that binding of autoantibodies to proteins involved in immune cell signalling and in within the vasculature might explain the autoimmune reactivity contributing to MIS-C pathology (2, 4).
1)Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-8.
2)Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, et al. The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19. Cell. 2020;183(4):968-81 e7.
3) Vella L, Giles JR, Baxter AE, Oldridge DA, Diorio C, Kuri-Cervantes L, et al. Deep Immune Profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. medRxiv. 2020.
4) Gruber CN, Patel RS, Trachtman R, Lepow L, Amanat F, Krammer F, et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C). Cell. 2020;183(4):982-95 e14.
Vahidy et al: Men are more likely to test positive, have complications, require ICU admission and mechanical ventilation and have higher mortality than females, independent of age.
Peckham et al: Meta-analysis of 3,111,714 reported global cases - males are 3x more likely to require ICU admission and have higher odds of death.
Vahidy FS, Pan AP, Ahnstedt H, Munshi Y, Choi HA, et al. (2021) Sex differences in susceptibility, severity, and outcomes of coronavirus disease 2019: Cross-sectional analysis from a diverse US metropolitan area. PLOS ONE 16(1): e0245556. https://doi.org/10.1371/journal.pone.0245556
Peckham, H., de Gruijter, N.M., Raine, C. et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun 11, 6317 (2020). https://doi.org/10.1038/s41467-020-19
Since publication, the FDA has rescinded its authorisation of bamlanivimab (LY-CoV555), due to its lack of efficacy against circulating variants of concern, particularly B.1.351 (South African), as a result of E484K substitution A,B. Eli Lilly are now pursuing the use of their combination therapy of bamlanivimab with etesevimab (LY-CoV016).
The antibody cocktail REGN-CoV2 showed sustained efficacy against tested variant strains and thus remains a viable treatment option. However, a mutational library scan by Starr et al. revealed that a single amino acid change (E406W) is all that is required for a future variant to escape this therapy C.
Circulating variants highlight the limited efficacy of monoclonal antibodies to an evolving virus, particularly in those which are restricted to the RBD. A diverse panel of monoclonal antibodies, which bind subdominant epitopes may be a more sustainable approach.
A – Wang, P et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. 2021. Nature. https://doi.org/10.1038/s41586-021-03398-2
B – Starr, T.N.et al. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal LY-CoV555 and its cocktail with LY-CoV016. 2021. Cell Reports Medicine. https://doi.org/10.1016/j.xcrm.2021.100255
C – Starr, T.N.et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. 2021. Science. https://doi.org/10.1126/science.abf9302
Bilich et al showed that IgG and IgA antibody responses declined during the six-month follow-up, raising concerns that humoral immunity against SARS-CoV-2 may not provide longterm protection. Anti-S1 antibody responses decrease over time, whereas anti-nucleocapsid antibody titres persist, this is important in the context of vaccine development focusing on the induction of immune responses to the RBD of the spike protein.
Bilich T, Nelde A, Heitmann JS, Maringer Y, Roerden M, Bauer J, et al. T cell and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term immune responses in COVID-19 convalescent individuals. Science Translational Medicine. 2021:eabf7517.
Zhou et al showed that serum IgM and IgG, especially in patients with moderate‐to‐high levels, declined significantly between week 4 to 10 after illness onset. Paper suggests that a decline in IgM may be an indicator of virus clearance. Although IgG levels declined to low levels within 11 weeks, they remained detectable.
Figueiredo‐Campos et al quantified IgM, IgG and IgA and showed that although titres reduced, IgG antibodies remained robust with confirmed neutralisation activity for up to 6 months
Zhou W, Xu X, Chang Z, Wang H, Zhong X, Tong X, Liu T, Li Y. The dynamic changes of serum IgM and IgG against SARS-CoV-2 in patients with COVID-19. J Med Virol. 2021 Feb;93(2):924-933. doi: 10.1002/jmv.26353. Epub 2020 Sep 28. PMID: 32706425; PMCID: PMC7404900.
Figueiredo‐Campos, P., Blankenhaus, B., Mota, C., Gomes, A., Serrano, M., Ariotti, S., Costa, C., Nunes‐Cabaço, H., Mendes, A.M., Gaspar, P., Pereira‐Santos, M.C., Rodrigues, F., Condeço, J., Escoval, M.A., Santos, M., Ramirez, M., Melo‐Cristino, J., Simas, J.P., Vasconcelos, E., Afonso, Â. and Veldhoen, M. (2020), Seroprevalence of anti‐SARS‐CoV‐2 antibodies in COVID‐19 patients and healthy volunteers up to 6 months post disease onset. Eur. J. Immunol., 50: 2025-2040. https://doi.org/10.1002/eji.202048970
Larger, blinded, randomized control trials are still ongoing to confirm the efficacy of CP treatment, the RECOVERY trial in Oxford is one such Phase 3 trial of CP (NCT04381936).
The RECOVERY trial in Oxford, with 5795 patients who were randomly allocated to receive convalescent plasma treatment and 5763 who received usual care alone, found that there was no statistically significant difference for 28-day mortality (24% for both groups, p-0.93) or the proportion of patients discharged from hospital within 28 days (66% CP vs 67% control, p=0.50) for the two groups. Additonally for patients without mechanical ventilation, there was no stastically significant difference in the intubation rate (28% CP vs 29% control, p=0.79).
The trial showed convalescent plasma therapy had no benefit to patients with COVID-19. As a result the UK's health service has stopped collecting convalescent plasma from patients who had recovered from COVID-19.
Additonally the NIH have halted a convalescent plasma trial for COVID-19 patients with mild symptoms stating that the "study shows that the treatment is safe, but provides no signifcant benefit in this group".
Rosado J, Pelleau S, Cockram C et al. Multiplex assays for the identification of serological signatures of SARS-CoV-2 infection: an antibody-based diagnostic and machine learning study. The Lancet Microbe 2021; doi: 10.1016/S2666-5247(20)30197-X.
Bertoglio F, Meier D, Langreder N et al. SARS-CoV-2 neutralizing human recombinant antibodies selected from –pre-pandemic healthy donors binding at RBD-ACE2 interface. Nature Communications 2021; doi: 10.1038/s41467-021-21609-2.
Sahin U, Muik A, Derhovnessian E et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell repsonses. Nature 2020; doi: 10.1038/s41586-020-2814-7.
Tian J-H, Patel N, Haupt R et al. SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nature Communications 2021; doi: 10.1038/s41467-020-20653-8.
Routhu NK, Cheedarla N, Gangadhara S et al. A modified vaccinia Ankara vector-based vaccine protects macaques from SARS-CoV-2 infection, immune pathology, and dysfunction in the lungs. Immunity 2021; doi: 10.1016/j.immuni.2021.02.001.
Gai J, Ma L, Li G et al. A potent neutralizing nanobody against SARS-CoV-2 with inhaled delivery potential. MedComm 2021; doi: 10.1002/mco2.60.
Hicks J, Klumpp-Thomas C, Kalish H et al. Serologic Cross-Reactivity of SARS-CoV-2 with Endemic and Seasonal Betacoronaviruses. Journal of Clinical Immunology. 2021. doi: https://doi.org/10.1007/s10875-021-00997-6
Klassan SA, Senefeld, JW, Johnson PW et al. The Effect of Convalescent Plasma Therapy on COVID-19 Patient Mortality: Systematic Review and Meta-analysis. medRxiv 2021; doi: 10.1101/2020.07.29.20162917.
Xiao T, Wang Y, Yuan J et al. Early Viral Clearance and Antibody Kinetics of COVID-19 Among Asymptomatic Carriers. Frontiers in Medicine. 2021. doi:https://doi.org/10.3389/fmed.2021.595773
Gontu A, Srinivasan S, Salazar E et al. Limited window for donation of convalescent plasma with high live-virus neutralizing antibodies for COVID-19 immunotherapy. Communications Biology 2021; doi: 10.1038/s42003-021-01813-y.
Iyer AS, Jones FK, Nodoushania A 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 2020; doi:10.1126/sciimmunol.abe0367.