Long-term Specific IgG Response to SARS-CoV-2 Nucleocapsid Protein in Recovered COVID-19 Patients

This study monitored the long-term immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in patients who had recovered from coronavirus disease (COVID)-19. Anti-nucleocapsid immunoglobulin G (anti-N IgG) titer in serum samples collected at a single (N = 302) or multiple time points (N = 229) 3-12 months after COVID-19 symptom onset or SARS-CoV-2 detection in respiratory specimens was measured by semiquantitative chemiluminescent microparticle immunoassay. The 531 patients (966 specimens) were classified according to the presence or absence of pneumonia symptoms. Anti N IgG was detected in 87.5% of patients (328/375) at 3 months, 38.6% (93/241) at 6 months, 23.7% (49/207) at 9 months, and 26.6% (38/143) at 12 months. The anti-N IgG seropositivity rate was significantly lower at 6, 9, and 12 months than at 3 months (P < 0.01) and was higher in the pneumonia group than in the non-pneumonia/asymptomatic group at 6 months (P < 0.01), 9 months (P = 0.04), and 12 months (P = 0.04). The rate started to decline 6-12 months after symptom onset. Anti-N IgG sample/cutoff index was positively correlated with age (r = 0.192, P < 0.01) but negatively correlated with interval between symptom onset and blood sampling (r = - 0.567, P < 0.01). These findings can guide vaccine strategies in recovered COVID-19 patients.

Citing Articles

Durability of Functional SARS-CoV-2-Specific Immunological Memory and T Cell Response up to 8-9 Months Postrecovery From COVID-19.

Trimbake D, Singh D, K Y, Babar P, S V, Tripathy A J Immunol Res. 2025; 2025:9743866.

PMID: 39963186 PMC: 11832264. DOI: 10.1155/jimr/9743866.

Seroprevalence of SARS-CoV-2 in wet market workers in Dhaka, Bangladesh in 2022.

Rahman M, Alam A, Sarkar S, Khan M, Mangtani P, Butt S IJID Reg. 2025; 14():100497.

PMID: 39810749 PMC: 11732135. DOI: 10.1016/j.ijregi.2024.100497.

Detrimental Effects of Anti-Nucleocapsid Antibodies in SARS-CoV-2 Infection, Reinfection, and the Post-Acute Sequelae of COVID-19.

Nakayama E, Shioda T Pathogens. 2025; 13(12.

PMID: 39770368 PMC: 11728538. DOI: 10.3390/pathogens13121109.

Seroprevalence of SARS-CoV-2 nucleocapsid antibody among sex workers during the 5th epidemic wave with Omicron variant in Chiang Mai, Thailand.

Hongjaisee S, Guntala R, Tangmunkongvorakul A, Ngo-Giang-Huong N, Khamduang W Heliyon. 2024; 10(17):e36807.

PMID: 39263051 PMC: 11388775. DOI: 10.1016/j.heliyon.2024.e36807.

A serological survey of COVID-19 among predominantly aboriginal residents of a tourist island in southern Thailand.

Sripaew S, Yasharad K, Rahari D, Feng W, Qian Z, Thanh H Trop Med Health. 2024; 52(1):57.

PMID: 39232844 PMC: 11373474. DOI: 10.1186/s41182-024-00617-0.

References

Tilocca B, Soggiu A, Sanguinetti M, Musella V, Britti D, Bonizzi L . Comparative computational analysis of SARS-CoV-2 nucleocapsid protein epitopes in taxonomically related coronaviruses. Microbes Infect. 2020; 22(4-5):188-194. PMC: 7156246. DOI: 10.1016/j.micinf.2020.04.002. View

Burbelo P, Riedo F, Morishima C, Rawlings S, Smith D, Das S . Sensitivity in Detection of Antibodies to Nucleocapsid and Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Coronavirus Disease 2019. J Infect Dis. 2020; 222(2):206-213. PMC: 7313936. DOI: 10.1093/infdis/jiaa273. View

Tso F, Lidenge S, Poppe L, Pena P, Privatt S, Bennett S . Presence of antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 in COVID-19 plasma. PLoS One. 2021; 16(3):e0247640. PMC: 7932539. DOI: 10.1371/journal.pone.0247640. View

Long Q, Liu B, Deng H, Wu G, Deng K, Chen Y . Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020; 26(6):845-848. DOI: 10.1038/s41591-020-0897-1. View

Flude B, Nannetti G, Mitchell P, Compton N, Richards C, Heurich M . Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections. Viruses. 2021; 13(2). PMC: 7923061. DOI: 10.3390/v13020312. View

Okada M, Takemoto Y, Okuno Y, Hashimoto S, Yoshida S, Fukunaga Y . The development of vaccines against SARS corona virus in mice and SCID-PBL/hu mice. Vaccine. 2005; 23(17-18):2269-72. PMC: 7115605. DOI: 10.1016/j.vaccine.2005.01.036. View

Lumley S, Wei J, ODonnell D, Stoesser N, Matthews P, Howarth A . The Duration, Dynamics, and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Responses in Individual Healthcare Workers. Clin Infect Dis. 2021; 73(3):e699-e709. PMC: 7929225. DOI: 10.1093/cid/ciab004. View

Bradley T, Grundberg E, Selvarangan R, LeMaster C, Fraley E, Banerjee D . Antibody Responses after a Single Dose of SARS-CoV-2 mRNA Vaccine. N Engl J Med. 2021; 384(20):1959-1961. PMC: 8008753. DOI: 10.1056/NEJMc2102051. View

Gao W, Tamin A, Soloff A, DAiuto L, Nwanegbo E, Robbins P . Effects of a SARS-associated coronavirus vaccine in monkeys. Lancet. 2003; 362(9399):1895-6. PMC: 7112457. DOI: 10.1016/S0140-6736(03)14962-8. View

10.

Yao L, Wang G, Shen Y, Wang Z, Zhan B, Duan L . Persistence of Antibody and Cellular Immune Responses in Coronavirus Disease 2019 Patients Over Nine Months After Infection. J Infect Dis. 2021; 224(4):586-594. PMC: 8243600. DOI: 10.1093/infdis/jiab255. View

11.

Feng X, Yin J, Zhang J, Hu Y, Ouyang Y, Qiao S . Longitudinal Profiling of Antibody Response in Patients With COVID-19 in a Tertiary Care Hospital in Beijing, China. Front Immunol. 2021; 12:614436. PMC: 8005580. DOI: 10.3389/fimmu.2021.614436. View

12.

Wheatley A, Juno J, Wang J, Selva K, Reynaldi A, Tan H . Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat Commun. 2021; 12(1):1162. PMC: 7896046. DOI: 10.1038/s41467-021-21444-5. View

13.

Turner J, Kim W, Kalaidina E, Goss C, Rauseo A, Schmitz A . SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Nature. 2021; 595(7867):421-425. DOI: 10.1038/s41586-021-03647-4. View

14.

Wu Z, McGoogan J . Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323(13):1239-1242. DOI: 10.1001/jama.2020.2648. View

15.

Vitale J, Mumoli N, Clerici P, De Paschale M, Evangelista I, Cei M . Assessment of SARS-CoV-2 Reinfection 1 Year After Primary Infection in a Population in Lombardy, Italy. JAMA Intern Med. 2021; 181(10):1407-1408. PMC: 8164145. DOI: 10.1001/jamainternmed.2021.2959. View

16.

Long Q, Tang X, Shi Q, Li Q, Deng H, Yuan J . Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020; 26(8):1200-1204. DOI: 10.1038/s41591-020-0965-6. View

17.

Guan W, Ni Z, Hu Y, Liang W, Ou C, He J . Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020; 382(18):1708-1720. PMC: 7092819. DOI: 10.1056/NEJMoa2002032. View

18.

Rogers T, Zhao F, Huang D, Beutler N, Burns A, He W . Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science. 2020; 369(6506):956-963. PMC: 7299280. DOI: 10.1126/science.abc7520. View

19.

Lin L, Luo S, Qin R, Yang M, Wang X, Yang Q . Long-term infection of SARS-CoV-2 changed the body's immune status. Clin Immunol. 2020; 218:108524. PMC: 7351676. DOI: 10.1016/j.clim.2020.108524. View

20.

Narasimhan M, Mahimainathan L, Araj E, Clark A, Markantonis J, Green A . Clinical Evaluation of the Abbott Alinity SARS-CoV-2 Spike-Specific Quantitative IgG and IgM Assays among Infected, Recovered, and Vaccinated Groups. J Clin Microbiol. 2021; 59(7):e0038821. PMC: 8218760. DOI: 10.1128/JCM.00388-21. View