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How Long Will COVID-19 Antibody Protection Last?

By Stuart M. Caplen, M.D.



A critical question for the world is how long will antibody protection after COVID-19 infection or vaccination last?


Other coronavirus infections such as SARS (severe acute respiratory syndrome) produce antibodies that can last a few years[1], while the coronavirus that causes the common cold may produce antibodies that last as little as a few months in some individuals.[2] However, having a high level of antibodies may not even be the most important component of immunity to COVID-19.


SARS-CoV-2 Virus, Antibody Production and Immunity


The coronavirus is named after the corona, or crown, of protein spikes that surrounds each viral particle. These spikes can attach to a cell’s membrane via the ACE2 (Angiotensin-Converting Enzyme 2) receptor located on many cells in the human body. The virus then breaches the cell membrane, allowing the virus to enter the cell and turn it into a living factory for making more viruses. Eventually the cell lyses (disintegrates), releasing the newly created viruses to infect other cells.[3]

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibodies are produced by T and B lymphocyte cells in the body during a COVID-19 infection.  T helper cells (CD4 T cells) help activate the B cells, which then become plasma cells and start producing antibodies.  T cells also  activate other immune cells and release cytokines, which are signaling molecules for controlling the immune system.  Other types of T cells called cytotoxic T cells (killer T cells or CD8 T cells) attack and destroy infectious viruses directly.[4,5] 



Neutralizing spike protein antibodies produced by the B and T cells can latch onto the SARS-CoV-2 protein spikes, and block the virus from attaching to the ACE2 receptors and infecting new cells. After a person gets infected, T and B cells are activated producing a neutralizing antibody response with immunoglobulin M (IgM), whose presence indicates an acute infection. Levels of IgM may be present a few days after symptoms start, but then drop over a few weeks. Immunoglobulin G (IgG) starts to rise typically 10 to 14 days after infection, and provides longer lasting immunity. The immune system also directs cytotoxic T cells to attack and try to destroy the virus. Memory T cells are formed after an infection, and are long lived. When presented with the same virus or bacteria in the future, memory T cells quickly produce more T helper and cytotoxic cells, which then activate B cells, and create antibodies to fight re-infection.[4,5,6] Long lived memory B cells may also be produced after an infection to create immunity. If an individual is re-exposed to the same virus, the memory B cells provide much more rapid and higher levels of antibody production than on the first exposure to the virus, which may help prevent serious reinfection.[7,8,9]



The immune system produces other SARS-CoV-2 antibodies in addition to the spike protein antibody in a further attempt to neutralize the virus. These antibodies appear not to be as important for immunity as the spike protein antibody. One issue in interpreting blood antibody test results is that some frequently used antibody tests, the Abbott and Roche tests as examples, test for nucleocapsid, or N protein antibodies that are bound up with the virus’ genetic material, because it is relatively easy to test for and is in large concentration in the blood. Other manufacturers’ tests are specific for the spike protein antibody, or for both the spike and the N protein antibodies.[7] It is the spike protein antibody that appears to confer some immunity. It is still a matter of debate whether levels of N antibody are a true marker for immunity from COVID-19 or not.[7] There are reports that these two SARS-CoV-2 antibodies appear to have different lifespans. In one prepublication study, the N antibody was found to be active for a shorter period of time than the spike antibody. It was found that at about 6 months after a COVID-19 infection, 50% of people would have a negative N protein antibody test, but 100% of the spike protein antibody tests would still be positive. It was estimated that it would take about 1.5 years until the spike antibody had disappeared in 50% of people. It was also suggested that measurement of the N antibody, especially some months after an infection, might spuriously indicate that antibodies were diminished, when they actually were still present.[8]


Unfortunately, there is conflicting data that demonstrates spike protein antibodies to SARS-CoV-2 fade after a shorter time. In fact, some people may recover without producing any detectable antibodies. In one prepublication study, SARS-CoV-2 IgG spike or N antibodies were found in 89.8% of recovered COVID-19 patients, but 10% of patients did not appear to develop any antibody immunity to COVID-19.[9] Another study found that 12.9% of symptomatic COVID-19 patients and 40% of individuals with asymptomatic COVID-19 infections became negative for IgG spike protein antibodies within two to three months after COVID-19 infection.[10] Another research team found that people who had low antibody levels during infection, had negative antibody titers after 50 days on average. Those with higher antibody levels during infection maintained those antibodies for up to 94 days, the endpoint of the study.[11]


While antibodies provide some immunity, many asymptomatic and mildly ill individuals don’t seem to produce large amounts or possibly even any long-lasting IgG antibodies. How are these people recovering from COVID-19, and are these antibodies even needed for long term immunity? Protection from serious disease in some people may be more dependent on T cell activation than antibodies to recover from the infection or prevent re-infection.[12] In one paper, helper CD4 T cells reactive to the SARS-CoV-2 virus were found in all patients who have had a COVID-19 infection, as well as 40-60% of non-infected individuals. 70% of infected individuals also had cytotoxic CD8 T cell activation.[13] Another prepublication study found activated CD4 helper T cells in 83% of COVID-19 infected patients, as well as 34% of non-infected people.[14] It is thought that T cell activation in patients who have not had COVID-19 may occur from cross-reactivity to other coronavirus infections, such as the common cold, which may offer some individuals protection against COVID-19.[15,16] A third prepublication study found that most individuals with asymptomatic or mild COVID-19 symptoms generated highly functional memory T cell responses, some without any antibody response, suggesting that the T cell responses might have helped cure the infection, and may prevent reinfection by COVID-19 in those individuals.[17]


In another recent study, memory B cells were found in patients recovering from COVID-19, most with low levels of circulating antibody.  The authors suggest that these memory B cells might rapidly produce potent antibodies to SARS-CoV-2 if the patient was re-exposed, helping to prevent reinfection.[7,8]


What Is Known About Immunity from COVID 19 infections?

  • As there is conflicting data, the answer is not yet known whether COVID-19 antibody protection is like SARS, lasting a few years, or more like that of the common cold which decreases rapidly with time in most people.

  • Measuring the N protein antibody, rather than the spike protein for antibody testing, may or may not be an accurate test of immunity. Testing for the N protein antibody, especially some months after an infection, may give falsely negative results due to its shorter lifespan than the spike protein antibody.

  • The presence of IgG antibodies, while conferring some immunity protection from COVID-19, may not be a true indication of immunity for everyone. Many individuals with mild or asymptomatic COVID-19 infection have a low or possibly no detectable antibody response. Their recovery from the infection may be based more on T cell responses, rather than neutralizing antibodies. Even with low antibody titers, these people may still have some protection against COVID-19 reinfection. The ability to produce or already have some T cell activation to COVID-19 may be one part of the picture that explains the great variability of this disease, from asymptomatic to life threatening.

  • Some people may have pre-existing activated T cells from other coronavirus infections that offer some protection against COVID-19 infections.

  • T cells originate from stem cells in the bone marrow and then travel to the thymus for maturation. The thymus shrinks as people age which reduces its ability to produce new T cells and is a part of increasing susceptibility to disease with aging.[18] This may partially explain the increased virulence of COVID-19 in the elderly.


  • Memory B cells may play a part in producing long term immunity to COVID-19.

  • The question of whether you can get infected twice with the virus is still an open one. There are some isolated case reports of this happening, but whether these were true reinfections or just relapses is still unclear. As time goes on it will become more evident whether COVID-19 reinfection is possible.[19,20]

  • A successful vaccine may need to boost both spike neutralizing antibodies, which may or may not rapidly wane, and more importantly activate T cell responses to be effective for any significant length of time. Some vaccines in development have already shown promise that they can stimulate both types of immunity.[24,25] Vaccines that also help produce memory B cells may be even more effective.[8]

Author’s Note: The entire topic of IgG neutralizing antibodies and T cell immunity in COVID-19 is not fully understood. Adding to the confusion is that many of the COVID-19 scientific articles are in prepublication. This means the articles have been published on the internet, but have not been peer reviewed by an expert in the field. As such, in the future some of the reported findings may be found to be incorrect, and the papers withdrawn. I have tried to distill current knowledge in this area to a reasonably coherent narrative, but as is the case with much of the world’s knowledge of COVID-19, we still have yet to reach a complete understanding of the disease.


References


[1] Wu LP, Wang NC, Chang YH, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007;13(10):1562‐1564. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851497/

[2] Marta Galanti, Jeffrey Shaman, Direct Observation of Repeated Infections With Endemic Coronaviruses, July, 7 2020, The Journal of Infectious Diseases, Retrieved from: https://doi.org/10.1093/infdis/jiaa392

[3] Chamary JV, Coronavirus Uses Spikes To Break Into Cells - Here’s How To Stop It, Forbes, Apr 17, 2020. Retrieved from: https://www.forbes.com/sites/jvchamary/2020/04/17/coronavirus-spike-protein/

[4] Cruickshank S, Davis DM, Coronavirus: how T cells are involved and what it might mean for vaccine development, The Conversation, June 11, 2020. Retrieved from: https://theconversation.com/coronavirus-how-t-cells-are-involved-and-what-it-might-mean-for-vaccine-development-140374


[5] Ghanchi A, T Cells, Teach Me Physiology, Last updated: May 26, 2020. Retrieved from https://teachmephysiology.com/immune-system/cells-immune-system/t-cells/

[6] Caplen S, Issues in the Creation, Testing and Use of a COVID-19 Vaccine, Fibonacci MD website, June 25, 2020. Retrieved from: https://www.fibonaccimd.com/post/issues-in-the-creation-testing-and-use-of-a-covid-19-vaccine

[7] Mandavilli A, Your Coronavirus Antibodies Are Disappearing. Should You Care?, The New York Times, July 26, 2020, Updated July 27, 2020. Retrieved from: https://www.nytimes.com/2020/07/26/health/coronvirus-antibody-tests.html?surface=home-discovery-vi-prg&fellback=false&req_id=13131991&algo=identity&imp_id=461902708&action=click&module=Science%20%20Technology&pgtype=Homepage

[8] Grandjean L, et al., Humoral Response Dynamics Following Infection with SARS-CoV-2,

medRxiv, July 16, 2020. Retrieved from https://doi.org/10.1101/2020.07.16.20155663


[9] Liu T, et al., Prevalence of IgG antibodies to SARS-CoV-2 in Wuhan - implications for the ability to produce long-lasting protective antibodies against SARS-CoV-2,medRxiv June 16, 2020. Retrieved from: https://doi.org/10.1101/2020.06.13.20130252


[10] Long, Q., Tang, X., Shi, Q. et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med (2020). Retrieved from: https://www.nature.com/articles/s41591-020-0965-6


[11] Seow J, et al., Longitudinal evaluation and decline of antibody responses in 1 SARS-CoV-2 infection, medRxiv, July 9, 2020. Retrieved from: https://www.medrxiv.org/content/10.1101/2020.07.09.20148429v1

[12] Gorvett Z, While the latest research suggests that antibodies against Covid-19 could be lost in just three months, a new hope has appeared on the horizon: the enigmatic T cell., BBC.Com, July 20, 2020. Retrieved from: https://www.bbc.com/future/article/20200716-the-people-with-hidden-protection-from-covid-19


[13] Grifoni A, et al. , Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals, Cell, May 14, 2020. Retrieved from: https://www.cell.com/cell/fulltext/S0092-8674(20)30610-3#secsectitle0020


[14] Braun J, et al., Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors,

medRxiv, April 17,2020. Retrieved from: https://doi.org/10.1101/2020.04.17.20061440


[15] Mitch Leslie M, T cells found in COVID-19 patients ‘bode well’ for long-term immunity, Science, May. 14, 2020. Retrieved from: https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity


[16] Le Bert N, et al., SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls, Nature, July 7,2020. Retrieved from: https://www.nature.com/articles/s41586-020-2550-z_reference.pdf

[17] Sekine T, et al., Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19, bioRxiv June, 29, 2020. Retrieved from https://doi.org/10.1101/2020.06.29.174888


[18] Can we turn back the clock on an aging thymus?, Walter and Eliza Hall Institute of Medical Research, Medical Express, December22, 2017. Retrieved from: https://medicalxpress.com/news/2017-12-clock-aging-Thymus.html#:~:text=The%20thymus%20starts%20deteriorating%20after,in%20a%20process%20called%20involution.


[19] Roy S. COVID-19 Reinfection: Myth or Truth? [published online ahead of print, 2020 May 29]. SN Compr Clin Med. 2020;1-4. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255905/

[20] Mandavilli A, Can You Get Covid-19 Again? It’s Very Unlikely, Experts Say, The New York Times, July 22, 2020. Retrieved from: https://www.nytimes.com/2020/07/22/health/covid-antibodies-herd-immunity.html


[21] Sahin U, Concurrent human antibody and TH1 type T-cell responses 2 elicited by a COVID-19 RNA vaccine, medRxiv, July 7, 2020. Retrieved from: https://www.medrxiv.org/content/10.1101/2020.07.17.20140533v1.full.pdf


[22] Folegatti P, 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, The Lancet, July 20, 2020. Retrieved from: https://doi.org/10.1016/S0140-6736(20)31604-4


[23] Mandavilli A, Can You Get Covid-19 Again? It’s Very Unlikely, Experts Say, The New York Times, July 22, 2020. Retrieved from: https://www.nytimes.com/2020/07/22/health/covid-antibodies-herd-immunity.html

[24] Sahin U, Concurrent human antibody and TH1 type T-cell responses 2 elicited by a COVID-19 RNA vaccine, medRxiv, July 7, 2020. Retrieved from: https://www.medrxiv.org/content/10.1101/2020.07.17.20140533v1.full.pdf


[25] Folegatti P, 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, The Lancet, July 20, 2020. Retrieved from: https://doi.org/10.1016/S0140-6736(20)31604-4


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ABOUT THE AUTHOR

Stuart M. Caplen, MD, FACEP, MSM

Dr. Caplen is a former emergency physician and emergency department medical director, now retired from clinical practice. His current interests include how quality is produced and maintained in health care, and he recently achieved greenbelt certification in lean/six sigma.

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